CN103649075A - 1,4-dihydropyridine-3,5-dicarboxylate derivatives, preparation methods and uses thereof - Google Patents

1,4-dihydropyridine-3,5-dicarboxylate derivatives, preparation methods and uses thereof Download PDF

Info

Publication number
CN103649075A
CN103649075A CN201280020936.XA CN201280020936A CN103649075A CN 103649075 A CN103649075 A CN 103649075A CN 201280020936 A CN201280020936 A CN 201280020936A CN 103649075 A CN103649075 A CN 103649075A
Authority
CN
China
Prior art keywords
group
yue
bases
alkyl
yue bases
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201280020936.XA
Other languages
Chinese (zh)
Other versions
CN103649075B (en
Inventor
张蕙
范明伟
孙亮
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xuanzhu Biopharmaceutical Co Ltd
Original Assignee
Xuanzhu Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xuanzhu Pharma Co Ltd filed Critical Xuanzhu Pharma Co Ltd
Priority to CN201280020936.XA priority Critical patent/CN103649075B/en
Publication of CN103649075A publication Critical patent/CN103649075A/en
Application granted granted Critical
Publication of CN103649075B publication Critical patent/CN103649075B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Disclosed are 1,4-dihydropyridine-3,5-dicarboxylate derivatives represented by the formula (I), preparation methods, and uses for preparing medicaments of treating/or preventing kidney injury, cardiovascular and/or endocrine system diseases. Pharmaceutical compositions comprising the said compounds are also provided. R1, R2, R3, R4, R5, R6, R7, R8, m, n1, n2, p and q in the formula (I) are as defined in the description.

Description

1,4-dihydropyridine-3,5-dicarboxylate derivatives, preparation methods and uses thereof
1,4- dichloropyridine-3,5-carboxylic-acid ester derivant and its preparation and application technical field
The invention belongs to pharmaceutical technology field, specifically related to 1,4- dihydropyridines -3,5- dicarboxylate compounds and preparation method thereof and they prepare be used to treating/or prevention injury of kidney, the medicine of cardiovascular and/or endocrine system disease in terms of application, and pharmaceutical composition and pharmaceutical preparation containing the compound.Background technology
Dihydropyridine calcium ion channel blocker has been used to treat the medicine of angiocardiopathy since being 1970s, its by with protein receptor binding, optionally block Ca in L-type or/and T- type calcium channels2+Interior stream, reduces intracellular Ca2+Concentration, so as to change cardiovascular function, plays a protective role to the heart, the cerebrovascular.Dihydropyridine calcium ion channel blocker has the cardioselective of height, and antihypertensive effect is clearly, applied widely, is clinically widely used, it has also become preferred antihypertensive drugs.
Dihydropyridines is the calcium ion channel blocker of the most frequently used treatment hypertension, acts on length according to it and pharmacological characteristic is broadly divided into three generations Expe Opin. Drug Metab. Toxicol. (2009) 5 (8): 981 -987 ) .The first generation is mainly traditional short-acting retarding agent, and it is nifedipine to represent medicine（Nifedipine), this kind of medicine acting duration is short, with stronger peripheral vascular dilating effect, causes flush, reflex tachycardia and periphery oedema.This kind of calcium ion channel blocker can produce quick, significant antihypertensive effect, can cause the blunt great fluctuation process of blood pressure, increase cardiac complication disease sometimes（Such as miocardial infarction）The risk of generation, with obvious heart negative effects, increases the danger that hyperpietic has a heart attack；It can also cause sympathetic reflex excited, cause myocardial oxygen consumption to increase, easily induce arrhythmia cordis, myocardial infarction.Second on behalf of middle effect retarding agent, extends calcium channel retardation and holds time, reduces acute dilatation vascular effect；One class is the Slow release formulations of first generation medicine, and representing medicine has Nifedipine controlled-release tablet（Nifedipine GITS), another kind of is long-acting calcium ion channel blocker, and representing medicine has Amlodipine（), amlodipine this kind of medicine acute vascular expands Zhang Yinfa side reaction almost disappears, and antihypertensive effect continues more than 24 hours.The main side reaction of second generation medicine is that lasting peripheral vascular expansion causes periphery oedema.The target of third generation calcium ion channel blocker is while maintaining long-acting antihypertensive effect, further to reduce periphery oedema incidence, representing medicine has Barnidipine（Barnidipine), Lercanidipine（Lercanidipine), Manidipine（Manidipine) etc..These medicines are compared with Amlodipine（Amlodipine) continuous action is long, and improves tolerance.
The development of L-type calcium ion channel blocker so that the pharmacological activity and pharmacokinetics feature of calcium ion channel blocker class medicine make moderate progress, but the various side effects of its long-term prescription are not addressed.
Research is found, T- types calcium channel is expressed in various arteries, vein, and with unlike L- types calcium channel, T- types calcium channel participates in the regulation of microcirculation, and microcirculation plays an important role (J Pharmacol Sci (2005) 99 in terms of regulation blood pressure, renal perfusion and coronary blood flow: 214-220 ) .In kidney microcirculation, L-type calcium channel is mainly distributed on kidney afferent glomerular arteriole, suppresses its effect and easily produces distensibility of blood vessel oedema side effect；And T- types calcium channel is distributed in kidney afferent glomerular arteriole He Kidney efferent glomerular arterioles simultaneously; suppress T- type calcium channels; microcirculation can be improved by balanced fluid statics; in the case of Bu Ying Xiang Kidney bead internal pressures; increase glomerular filtration rate(GFR; distensibility of blood vessel oedema is reduced, the effect of long-term kidney organ's protection is played.On the other hand, T- types calcium ion channel blocker can also adjust heartbeat, adjustment VPV, with cardioprotection.
L-type and the dual calcium ion channel blocker of T- types both have the effect of reducing blood pressure, and can slow down tachycardia again, reduce oedema, with heart, Renoprotective Effect (Hypertension. 2009; 53: 592-594 ) .Clinical research shows, L-type and the dual calcium ion channel blocker mibefradil of T- types（Mibefradil) it is effective depressor and anti-ischemic medicine, the side reaction that the conventional calcium ion channel blocker of reduction triggers, vasodilator smooth muscle, can reducing heart rate, improvement cardiac function (Exp. Opin. Invest. Drugs (1997) 6 (5) while myocardial contractive power is not reduced: 569-582 ) .Mibefradil and L-type and the dual calcium ion channel blocker Efonidipine of T- types（Efonidipine therapeutic effect) further demonstrate above-mentioned deduction (Cardiovascular Drug Reviews, 2002,20 (1):81-92 ) .But mibefradil (Mibefradil) because medicine acts on listing and quit listing less than 1 year each other.Therefore, develop more securities more preferably, the compound with L-type and the dual calcium channel retardation of T- types be urgent clinical needs.Block T- type calcium channels while blocking L-type calcium channel, not only produce the effectiveness for the treatment of hypertension, solve the side effect that L-type calcium ion channel blocker can not overcome, moreover it is possible to play the dirty effects of cardioprotection, Kidney.The content of the invention
The present inventor using develop it is excellent have antihypertensive effect and to heart and ' the dirty medicine with protective effect is target; by substantial amounts of experiment; it is found that a class antihypertensive effect significantly can simultaneously maintain the 1 with L-type and the dual calcium channel retardation of T- types of long-acting antihypertensive effect; 4- dihydropyridines -3; 5- dicarboxylate derivatives, this completes the present invention.
Therefore, the present invention provides following formulas（I compound and its pharmaceutically acceptable salt and stereoisomer shown in)：
Wherein：
R1And R4It is each independently selected from following one group of group：Amino, cyano group, and it is unsubstituted or by 1 to 3 substituent Q1Substituted .6 alkyl, CMAlkoxy C1-3Alkyl, C2-6Alkenyl or C2_6Alkynyl, and carbon atom therein can be optional（I.e., optionally）By 1 ~ 30, S (0)x、 N(H)X、 NCH3Or C (O) is replaced, wherein x is selected from 0,1 or 2; Q1Selected from following one group of group：Element, hydroxyl, amino, cyano group, carboxyl and C!_6Alkoxy；
R2Selected from unsubstituted or by 1 to 3 substituent Q2Substituted ^_6Alkyl, C3_8Cycloalkyl Q)6Alkyl or 3-8 circle heterocycles bases Co_6Alkyl, Q2Selected from following one group of group：Halogen, hydroxyl, amino, alkoxy, and by the alkyl and d_ of 1 to 3 element substitution6Alkoxy； R3Selected from following one group of group：Hydrogen, element, hydroxyl, cyano group, nitro and C6Alkylamidoalkyl；
R5And R6It is each independently selected from unsubstituted or by 1 to 3 substituent Q3Substituted CM alkyl or C3_8Cycloalkyl C0_6Alkyl, Q3Selected from following one group of group：Halogen, hydroxyl, amino and alkoxy；
R7And R8It is each independently selected from following one group of group：Hydrogen,（^-6Alkyl, it is unsubstituted or by 1 to 3 substituent Q4Substituted aryl Co_6Alkyl, and it is unsubstituted or by 1 to 3 substituent Q4Substituted 3-8 circle heterocycles bases C6Alkyl, and R7And R8It is asynchronously hydrogen, Q4Selected from following one group of group：Halogen, hydroxyl, cyano group, nitro, amino, CM alkyl, the d. of 1 to 3 halogen substitution6Alkyl, d.6Alkoxy and d_6Alkylamidoalkyl；
M is selected from 1,2 or 3, when m is 2 or 3, R3Can be with identical or different； n1And n2It is each independently selected from 1 to 5 integer, and n1And n2Can not be 2,4 and 5 simultaneously;And
P and q are each independently selected from 0,1,2 or 3, but when q is 0, R7And R8Can not be phenyl simultaneously.
The present invention also provides pharmaceutical composition and pharmaceutical preparation containing the logical formula (I) compound or its pharmaceutically acceptable salt or their stereoisomer.
The present invention also provides the logical formula (I) compound or its pharmaceutically acceptable salt or their stereoisomer and the pharmaceutical composition containing the logical formula (I) compound or its pharmaceutically acceptable salt or their stereoisomer, is used as treatment/or pre- anti-Kidney damages, the medicine of cardiovascular and/or endocrine system disease.
The present invention also provide the logical formula (I) compound or its pharmaceutically acceptable salt or their stereoisomer and pharmaceutical composition containing the logical formula (I) compound or its pharmaceutically acceptable salt or their stereoisomer prepare be used to treating/or prevention injury of kidney, the medicine of cardiovascular and/or endocrine system disease in terms of application.
The present invention also provides treatment/or prevention injury of kidney, the method for cardiovascular and/or endocrine system disease, including the step of give the logical formula (I) compound or its pharmaceutically acceptable salt or their stereoisomer of object effective dose in need or pharmaceutical composition containing the logical formula (I) compound or its pharmaceutically acceptable salt or their stereoisomer. The present invention also provides the preparation method of the logical formula (I) compound, and methods described includes following step
Or
(I) R in reacting flow chart1 R2、 R3、 R4、 R5、 R6、 R7、 R8、 m、 n1 , n2, p and q as defined hereinabove；2=R of raw material5MgX, wherein X are Br or I；Raw material 2 ,=R5MgI, Step 1:The preparation of intermediate 1
Method 1:
Make raw material 1 and the (RMgBr of raw material 2）Intermediate 1 is obtained in nucleophilic substitution occurs under low temperature such as-30-10 °C.
Method 2:
Make raw material Γ and raw material 2,（RMgBr）Generation nucleophilic substitution obtains intermediate 1-1, make itself and HA (acid, for general inorganic acid or organic acid, such as hydrochloric acid, nitric acid, sulfuric acid, acetic acid, formic acid, maleic acid, tartaric acid, Yue sulfonic acid or fumaric acid) carry out salt-forming reaction, obtain intermediate 1-2, coupling reaction is occurred into for obtained intermediate 1-2 and raw material 3, intermediate 1-3 is obtained, then by intermediate 1-3 reducing agents（Such as LiAlH4、 NaBH4Deng hydride ion reducing agent）Reduction, obtains intermediate 1.
Step 2:The preparation of intermediate 2
Make raw material 4, raw material 5 and raw material 6 in organic solvent（Such as ethanol, Yue alcohol, isopropanol, butanol, the alcohols solvent such as ethylene glycol）Middle backflow carries out condensation reaction, intermediate 2-1 is obtained, by it in alkali (such as NaOH, NaHC03Deng) in the presence of be hydrolyzed, obtain intermediate 2.
Step 3:Formula（I) the preparation of compound
Make intermediate 2 in such as-40-10 °C of low temperature and acid halide reagents（Such as thionyl chloride, acryloyl chloride）Reaction, then with intermediate 1 in the basic conditions（In the presence of such as sodium acid carbonate, sodium hydroxide）In low temperature, such as-40-10 °C are hydrolyzed reaction, obtain formula（I) compound.In the present invention, term " halogen " refers to fluorine, chlorine, bromine or iodine.
In the present invention, term " C1-6Alkyl " represents the straight or branched alkyl containing 1 to 6 carbon atom, preferably CM alkyl, such as alkyl, C2_3Alkyl, alkyl；The example includes but is not limited to such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, 2- methyl butyls, neopentyl, 1- ethyl propyls, n-hexyl, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3, the Yue bases butyl of 3- bis-, 2,2- dimethylbutyls, 1, the Yue bases butyl of 1- bis-, 1, the Yue bases butyl of 2- bis-, 1,3- bis- Yue bases butyl, 2,3- dimethylbutyls, 2- ethyl-butyls, the Yue base propyl group of 1,2- bis- etc..
In the present invention, term " Co-6Alkyl " represents the straight or branched alkyl containing 0 to 6 carbon atom, when carbon number is 0, represents a key；It is preferred that QM alkyl, such as C () _3Alkyl, most preferably C._2Alkyl.
In the present invention, term " C3-8Cycloalkyl " refers to that the paraffin section of 3 ~ 8 carbon atoms removes monovalence cyclic alkyl, preferably C derived from a hydrogen atom3_7Cycloalkyl, such as C5_7Cycloalkyl, C6Cycloalkyl, C5_6Cycloalkyl etc.；The example includes but is not limited to such as cyclopropyl, cyclobutyl, 1- Yue tetramethylcyclobutyls, cyclopenta, cyclohexyl, suberyl, cyclooctyl.
In the present invention, term " C^ alkoxies " refers to what is be connected by oxygen atom with other structures " _6Alkyl " group, preferably（^-4Alkoxy, such as C3Alkoxy, C alkoxies etc.；The example includes but is not limited to such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, amoxy, neopentyl oxygen, hexyloxy.
In the present invention, term " C2_6Alkenyl " refers to the straight or branched that the carbon number containing double bond is 2 ~ 6; also including ring-type; alkyl, such as vinyl, 1- acrylic, 2- acrylic, 1- cyclobutenyls, 2- cyclobutenyls, 1- pentenyls, 2- pentenyls, 3- pentenyls, 1- hexenyls, 2- hexenyls, 3- hexenyls, cyclopropanyl, cyclopentenyl, cyclohexenyl group.
In the present invention, term " C2-6Alkynyl " refers to the straight or branched that the carbon number containing three keys is 26; also including ring-type; alkynyl, such as acetenyl, propinyl, 2- butynyls, 2- pentynyls, 3- pentynyls, 2- hexin bases, 3- hexin bases, cyclopropyne base, cyclobutynyl, ring pentynyl, hexamethylene alkynyl.
In the present invention, term " alkylamidoalkyl " refers to " d_6Alkyl-CO-NH- " groups.In the present invention, term " aryl " refers to 6 ~ 10 unit monocycles or di-aromatics cyclic group, such as phenyl, naphthyl.
In the present invention, term " 3-8 heterocyclic radicals " refers to heteroatomic 3 ~ 8 yuan of saturations or unsaturated cyclic group that nitrogen, oxygen or sulphur are selected from containing one or more, such as 3-6 circle heterocycles bases, more preferably 5-6 circle heterocycles base；The example includes but is not limited to such as Oxyranyle, dioxirane base, thiirane base, aziridine base, 2H- aziridine base, diazacyclo propyl, 3H- diazacyclos acrylic, oxaza propyl, oxetanyl, 1,2- dioxies N2012/000577 azetidinyls,Thietane base, 1,2- dithia cyclobutane bases,Azetidinyl, 1,2- diazetidine bases,Diazete base, 1,2- diazetine bases,Furyl,Tetrahydrofuran base,Thienyl, 2,5- dihydro-thiophene bases,Tetrahydro-thienyl,Pyrrole radicals,Pyrrolin base,Pyrrolidinyl, 1,3- dioxolane bases, 1,3- dioxole -2- ketone groups, 1,2- dithiole bases, 1,3- dithiolane bases,Imidazole radicals, 4,5- glyoxalidine bases,Imidazolidinyl,Pyrazolyl, 4,5- pyrazoline bases,Pyrazolidinyl,Drink oxazolyl, 4,5- dihydros feed oxazolyl,Different ^ oxazolyls, 4,The different food in one's mouth oxazolyl of 5- dihydros, 2,Different fish sticking its mouth out of the water the oxazolyl of 3- dihydros, 1,2,3- oxadiazoles bases, 1,2,5- feeds di azoly,Thiazolyl, 4,5- dihydro-thiazolyls,Isothiazolyl, 1,2,3- thiadiazolyl groups, 1,2,4- thiadiazolyl groups, 1,3,4- thiadiazolyl groups, 1,2,3- triazolyls, 1,2,4- triazolyls,Tetrazole radical,2H- pyranoses,2H- pyran-2-one bases, 3,4- dihydro -2H- pyranoses,4H- pyranoses,THP trtrahydropyranyl,4H- pyrans -4- ketone groups,Pyridine radicals,2- pyriconyls,4- pyriconyls,Hydrogenated pyridine ketone group,Piperidyl, 1,4- Dioxin bases, 1,4- dithiins bases, 1,4- oxathiin bases, 1,4- dioxane bases, 1,3- dioxane bases, 1,3- thioxane bases, 2H-l,2-p oxazines bases, 4H-l,2-p oxazines bases, 6H-1,2- " oxazines bases, 2H-1,3- " oxazines bases, 4Η-1,3-' oxazines bases, 6Η-1,3- feeds piperazine base, 2Η-1,4- drinks piperazine base, 4Η-1,4- drinks piperazine base, 5,The Η -1 of 6- dihydros -4,3- feeds piperazine base,Morpholinyl, 2Η-1,3- thiazinyls, 4Η-1,3- thiazinyls, 5,6- dihydros -4H--thiazinyl, 6Η-1,3- thiazinyls, 2Η-1,4- thiazinyls, 4Η-1,4- thiazinyls,Pyridazinyl,Pyrimidine radicals,Pyrazinyl,Piperazinyl, 1,2,3- triazine radicals, 1,2,4- triazine radicals, 1,3,5- triazine radicals, 1,2,4,5- tetrazine bases,Oxepin base,Thia cycloheptatriene base, 1,4- dioxane sarohornene bases,Azepine cycloheptatriene base, 1,2- diaza cycloheptatriene bases, 1,3- diaza cycloheptatriene bases, 1,4- diaza cycloheptatriene bases,Azepine cyclooctatetraenyl, 1,4- dihydros -1,4- diazocine trialkenyls etc..The wherein heterocyclic radical of saturation preferably such as aziridine base, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, hydrogenated pyridine ketone group, piperidyl, piperazinyl, Oxyranyle, tetrahydrofuran base, tetrahydro-thienyl, 1, 3- dioxolane bases, 1, 3- dithiolane bases, THP trtrahydropyranyl, 1, 4- dioxane bases, 1, 3- dioxane bases, 1, 3- thioxane bases, oxaza propyl, morpholinyl etc., undersaturated heterocyclic radical preferably such as pyridine radicals, furyl, thienyl base, pyrrole radicals, ^ oxazolyls, thiazolyl and thiadiazolyl group etc.. In a preferred embodiment of the logical formula (I) compound of the present invention, R1And R4It is each independently selected from following one group of group：Amino, cyano group, and unsubstituted or substituted base Q1Substituted ^^ alkyl, d_3Alkoxy d_2Alkyl, C2-4Alkenyl and C2_4Alkynyl, and carbon atom therein can be with optional by 0, S (0)x、 N(H)X、 NCH3Or C (O) is replaced, wherein x is selected from 0,1 or 2; Q1Selected from following one group of group：Halogen, hydroxyl, amino, carboxyl and C1-4Alkoxy.
In the logical formula (I) compound further preferred embodiment of the present invention, R1And R4It is each independently selected from following one group of group：Amino, cyano group, and unsubstituted or substituted base Q1Substituted d_4Alkyl and d_4Alkoxy, and carbon atom therein can be with optional by 0, N (H)xOr C (O) is replaced, wherein X is selected from 0,1 or 2; Q1Selected from following one group of group：Halogen, hydroxyl, amino and Ci.4 alkoxies.
In a preferred embodiment of the logical formula (I) compound of the present invention, R2Selected from unsubstituted or substituted base Q2Substituted CMAlkyl, C6Cycloalkyl Q)-4The heterocyclic radical Q of alkyl or 3-6 member saturations) _4Alkyl, Q2Selected from following one group of group：Halogen, hydroxyl, amino, CM alkoxies, and by the d_ of element substitution4Alkyl and（1-4Alkoxy.
In the logical formula (I) compound further preferred embodiment of the present invention, R2Selected from following one group of group：Unsubstituted or substituted base Q2Substituted CMAlkyl, C3_6Cycloalkyl 0) _2The heterocyclic radical .2 alkyl of alkyl or 5-6 member saturations, Q2Selected from following one group of group：Fluorine, chlorine, hydroxyl, amino, CMAlkoxy, and the C replaced by fluorine and/or chlorineMAlkyl and CMAlkoxy.
In a preferred embodiment of the logical formula (I) compound of the present invention, R3Selected from hydrogen, halogen, hydroxyl, cyano group, nitro or CM alkylamidoalkyls.
In the logical formula (I) compound further preferred embodiment of the present invention, R3Selected from hydrogen, halogen or nitro.
In a preferred embodiment of the logical formula (I) compound of the present invention, R5And R6It is each independently selected from unsubstituted or substituted base Q3Substituted CM alkyl or C3_6Cycloalkyl QM protective embankment bases, Q3Selected from following one group of group：Face element, hydroxyl, amino and alkoxy.
In the logical formula (I) compound further preferred embodiment of the present invention, R5And R6It is each independently selected from unsubstituted or substituted base Q3Substituted CMAlkyl or C3_6Cycloalkyl CQ_2Alkane Base, Q3Selected from following one group of group：Halogen, hydroxyl, amino and C1-2Alkoxy.
In a preferred embodiment of the logical formula (I) compound of the present invention, R7And R8It is each independently selected from following one group of group：Hydrogen, CMAlkyl, unsubstituted or substituted base Q4Substituted aryl Q) _4Alkyl, and unsubstituted or substituted base Q4Substituted 3-6 circle heterocycles base C (alkyl, Q4Selected from following one group of group：1 element, hydroxyl, amino, CM alkyl, and the C being optionally substituted by halogenMAlkyl and（Alkoxy.
In the logical formula (I) compound further preferred embodiment of the present invention, R7And R8It is each independently selected from hydrogen, CM alkyl, unsubstituted or substituted base Q4Substituted aryl CQ_2Alkyl, or unsubstituted or substituted base Q4Substituted 5-6 circle heterocycles bases CQ_2Alkyl, Q4Selected from following one group of group：Halogen, hydroxyl, amino, C1-3Alkyl, and the C being optionally substituted by halogen1-3Alkyl and alkoxy.
In the preferred embodiment of the logical formula (I) compound of the present invention, m is 1 or 2.
In the preferred embodiment of the logical formula (I) compound of the present invention, n1And n2It is each independently selected from 1,2 or 3, particularly 1 or 2.
In another preferred embodiment of the logical formula (I) compound of the present invention,
R1And R4It is each independently selected from following one group of group：Amino, cyano group is unsubstituted or by 1 to 3 substituent Q1Substituted CMAlkyl, d-3Alkoxy d_2Alkyl, C2_4Alkenyl or C2-4Alkynyl, and carbon atom therein can be optionally by 130, S (0)x、N(H)x、NCH3Or C (O) is replaced, wherein X is selected from 0,1 or 2; Q1Selected from following one group of group：Halogen, hydroxyl, amino, carboxyl and CMAlkoxy；
R2Selected from unsubstituted or by 1 to 3 substituent Q2Substituted C1-4Alkyl, C3-6Cycloalkyl CQ.4The heterocyclic radical Co. of alkyl or 3-6 member saturations4Alkyl, Q2Selected from following one group of group：Halogen, hydroxyl, amino,（：Alkoxy, and by the ^^ alkyl and C of 1 to 3 element substitutionMAlkoxy；
R3Selected from following one group of group：Hydrogen, halogen, hydroxyl, cyano group, nitro and（^_4Alkylamidoalkyl；
R5And R6It is each independently selected from unsubstituted or by 1 to 3 substituent Q3Substituted CMAlkyl or C3.6Cycloalkyl Q alkyl, Q3Selected from following one group of group：Halogen, hydroxyl, Amino and ^-4Alkoxy；
R7And R8It is each independently selected from following one group of group：Hydrogen, CMAlkyl, it is unsubstituted or by 1 to 3 substituent Q4Substituted aryl QM alkyl, and it is unsubstituted or by 1 to 3 substituent Q4Substituted 3-8 circle heterocycles base QM alkyl, and R7And R8It is asynchronously hydrogen, Q4Selected from following one group of group：Halogen, hydroxyl, amino, CM alkyl, the CM alkyl and C of 1 to 3 halogen substitutionMAlkoxy；
M is selected from 1,2 or 3, when m is 2 or 3, R3Can be with identical or different； n1And n2It is each independently selected from 1 to 4 integer, and n1And n2Can not be 2 and 4 simultaneously;And
P and q are each independently selected from 0,1,2 or 3, but when q is 0, R7And R8Can not be phenyl simultaneously.
In another preferred embodiment of the logical formula (I) compound of the present invention,
R1And R4It is each independently selected from following one group of group：Amino, cyano group, and it is unsubstituted or by 1 to 3 substituent Q1Substituted CMAlkyl and (1-4Protective embankment epoxide, and carbon atom therein can optionally by 130,1^ (11 or（(0) replace, wherein X is selected from 0,1 or 2;
Q1Selected from following one group of group：Halogen, hydroxyl, amino and CMAlkoxy；
R2Selected from following one group of group：It is unsubstituted or by 1 to 3 substituent Q2Substituted CMAlkyl, cyclopropyl, Cvclopropvlmethvl, cyclopropylethyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, pyrrolidinyl Yue bases and morpholinyl methyl, Q2Selected from following one group of group：Fluorine, chlorine, hydroxyl, amino,（Alkoxy, and the d_ replaced by 1 to 3 fluorine and/or chlorine4Alkyl and CM alkoxies；
R3Selected from following one group of group：Hydrogen,！Element and nitro；
R5And R6It is each independently selected from unsubstituted or by 1 to 3 substituent Q3Substituted CM alkyl or C3_6Cycloalkyl C0_2Alkyl, Q3Selected from following one group of group：Halogen, hydroxyl, amino and alkoxy；
R7And R8It is each independently selected from hydrogen, methyl, ethyl is unsubstituted or by 1 to 3 substituent Q4Substituted aryl CG_2Alkyl, and it is unsubstituted or by 1 to 3 substituent Q4Substituted 3-6 circle heterocycles base Co.2 alkyl, and R7And R8It is asynchronously hydrogen, Q4Selected from following one Group group：Halogen, hydroxyl, amino, C1-3Alkyl, and the alkyl and alkoxy that 1 to 3 halogen replaces；
M is each independently selected from 1,2 or 3, when m is 2 or 3, R3Can be with identical or different；
n1And n2It is each independently selected from 1,2 or 3, and n1And n2Can not be 2 simultaneously;And
P and q are each independently selected from 0,1,2 or 3, but when q is 0, R7And R8Can not be phenyl simultaneously.
In another preferred embodiment of the logical formula (I) compound of the present invention,
R1And R4It is each independently selected from following one group of group：It is unsubstituted or by 1 to 3 substituent Q1Substituted methyl, ethyl and ethyoxyl Yue bases, and carbon atom therein can optionally by 1 ~ 30,：^ (1 or（：(0) replace, wherein X is selected from 1 or 2; Q1Selected from following one group of group：Halogen, hydroxyl, amino, methoxyl group and ethyoxyl；
R2Selected from following one group of group：It is unsubstituted or by 1 to 3 substituent Q2Substituted Yue bases, ethyl, isopropyl, cyclopropyl, Cvclopropvlmethvl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, pyrrolidinyl Yue bases and morpholinyl Yue bases, Q2Selected from following one group of group：Fluorine, chlorine, hydroxyl, amino, CMAlkoxy, and the CM alkyl and d. replaced by 1 to 3 fluorine and/or chlorine4Alkoxy；
R3Selected from following one group of group：Hydrogen, fluorine, chlorine and nitro；
R5And R6It is each independently selected from unsubstituted or by 1 to 3 substituent Q3Substituted Yue bases or ethyl, Q3Selected from following one group of group：Fluorine, chlorine, hydroxyl, amino, Yue epoxides and ethyoxyl；
R7And R8It is each independently selected from following one group of group：Hydrogen, Yue bases, ethyl, and it is unsubstituted or by 1 to 3 substituent Q4Substituted phenyl CQ_2Alkyl, pyridine radicals CQ_2Alkyl, furyl CQ_ 2 alkyl, thienyl CG— 2Alkyl, pyrrole radicals CG.2Alkyl, thiazolyl CG.2Alkyl and thiadiazolyl group Co_2Alkyl, and R7And R8It is asynchronously hydrogen, Q4Selected from following one group of group：Fluorine, chlorine, hydroxyl, amino, Yue bases, ethyl, fluoro Yue bases, difluoro Yue bases, trifluoromethyl, Yue epoxides and ethyoxyl； M is selected from 1,2 or 3, when m is 2 or 3, R3Can be with identical or different；
n1For 1,2 or 3, n2For 1;
P and q are each independently selected from 0,1,2 or 3, when q is 0, R7And R8Can not be phenyl simultaneously.
In another preferred embodiment of the logical formula (I) compound of the present invention,
R1And R4It is each independently selected from unsubstituted or by 1 to 3 substituent Q1Substituted methyl, ethyl or ethyoxyl Yue bases, Q1Selected from fluorine, chlorine, amino, Yue epoxides or ethyoxyl； R2Selected from unsubstituted or by 1 to 3 substituent Q2Substituted Yue bases or ethyl, Q2Selected from fluorine, chlorine, Yue bases, Yue epoxides, or methoxyl group, the ethyoxyl replaced by 1 to 3 fluorine, chlorine；
R3Selected from hydrogen, chlorine or nitro；
R5Selected from unsubstituted or by 1 to 3 substituent Q3Substituted methyl or ethyl, Q3Selected from fluorine, chlorine, hydroxyl or amino；
R6Selected from unsubstituted or by 1 to 3 substituent Q3Substituted Yue bases, Q3Selected from fluorine, chlorine, hydroxyl or amino；
R7And R8It is each independently selected from hydrogen, it is unsubstituted or by 1 to 3 substituent Q4Substituted phenyl, benzyl, pyridine radicals, furyl, thienyl, thiazolyl or pyrrole radicals, and R7And R8It is asynchronously hydrogen,
Q4Selected from fluorine, chlorine, hydroxyl, amino, Yue bases, trifluoro Yue bases or methoxyl group；
M is 1;
n1For 1 or 2, n2For 1;
P is and q is each independently selected from 0,1 or 2, when q is 0, R7And R8Can not be phenyl simultaneously.
In the present invention, specific preferred logical formula (I) compound includes following compounds and their pharmaceutically acceptable salts and their stereoisomer:
In an embodiment of the logical formula (I) compounds process for production thereof of the present invention, formula of the present invention（I) compound can be prepared for example, by step in detail below：
Reaction process：
, or
( I )
I in reacting flow chart1、 R2、 R3、 R4、 R5、 R6、 R7、 R8、 m、 n n2, p and q as defined hereinabove；2=R of raw material5MgX, wherein X are Br or I；Raw material 2 ,=R5MgI, Reactions steps：
Step 1:The preparation of intermediate 1
Method 1:
In under low temperature such as -30 ~ -10 °C, by (1 equivalent of raw material 1）It is dissolved in organic solvent（Such as THF (tetrahydrofurans）, ether, 1,4- dioxane, DMF (two Yue base formamides）, DMSO (two Yue sulfoxides）Or acetonitrile etc.）In, resulting solution is added drop-wise to (2 equivalents of raw material 2）In solution in the organic solvent, stirring reaction obtains intermediate 1.
Method 2:
By raw material 1,（1 equivalent）In organic solvent（Such as THF, ether, 1,4- dioxane, DMF, DMSO or acetonitrile etc.）In solution Slow be added to raw material 2 slowly,（2 equivalents）In organic solvent（Such as ether, Isosorbide-5-Nitrae-dioxane, acetonitrile etc.）In solution in, in low temperature (- 30-10.C, such as -20 °C) stirring reaction, obtain intermediate 1-1 crude products.
Then above-mentioned crude product is dissolved in organic solvent such as 1,4- dioxane（Or ether, second Nitrile etc.）In, HC1 gases are passed through, stirring reaction is stayed overnight, obtain intermediate 1-2。
By intermediate 1-2 (1 equivalent), raw material 3 (1.1 equivalent), DIEA (DIPEA, 2 equivalents）With organic solvent such as DMF in 0 °C of stirring, HATU (2- (7- azos BTA)-Ν, Ν, Ν ', Ν '-four Yue base urea hexafluorophosphoric acid esters, 1.1 equivalents are added）, it is stirred overnight, obtains intermediate 1-3.
By reducing agent such as LiAlH4(3 equivalent) and solvent such as THF are in stirring under under cryogenic conditions such as-30-10 °C, then instill solution of the intermediate 1-3 (1 equivalent) in the organic solvent, and stirring reaction obtains intermediate 1.
Step 2:The preparation of intermediate 2
Raw material 4, raw material 5 and raw material 6 are dissolved in organic solvent (such as ethanol, methanol, isopropanol, butanol, the alcohols solvent such as ethylene glycol）In, the inorganic bases such as ammonium hydrogen carbonate, sodium acid carbonate, sodium hydroxide are optionally added, return stirring reaction obtains intermediate 2-1.Intermediate 2-1 is dissolved in organic solvent（The alcohols solvent such as methanol, ethanol, isopropanol, butanol or ethylene glycol）, stirring is lower to add the alkali such as NaOH aqueous solution, and stirring reaction obtains intermediate 2.
Step 3:Formula（I) the preparation of compound
Under such as -40 ~ -10 °C of low temperature, thionyl chloride Slow is added drop-wise to the organic solvent of intermediate 2 slowly（The organic solvent of low polarity such as dichloro Yue alkane, ethyl acetate, methyl tertiary butyl ether(MTBE) or toluene) in solution reaction to clarifying, reaction solution rotary evaporated to dryness is obtained into crude product.Make gained crude product with intermediate 1 in alkalescence（Such as sodium acid carbonate, sodium hydroxide are present）Under the conditions of in such as-40-10 °C stirring reactions of low temperature, obtain formula（I) compound.Formula (I) compound of the present invention or its stereoisomer can in a free form or the form of its pharmaceutically acceptable salt is used.The aobvious alkalescence of formula (I) compound of the present invention, can be with inorganic acid or organic acid formation acid-addition salts, including but not limited to such as hydrochloride, hydrofluoride, hydrobromate, hydriodate, sulfate, trifluoroacetate, benzene sulfonate, mesylate, trifluoro Yue sulfonate, esilate, carbonate, nitrate, phosphate, phosphite, maleate, tartrate, citrate, acetate, benzene Yue hydrochlorates, esilate, fumarate, oxalates, gluconate, hydroxyl acetate, isethionic acid, lactate, Lactobionate, breast Sugar lime, malate, Yue sulfonate, succinate, tosilate, glycinate, trimethylglycine salt, arginine salt, ornithine salt, glutamate, aspartate etc..
Due to there is asymmetric carbon atom in formula (I) compound of the present invention or its pharmaceutically acceptable salt structure, can exist with optical isomeric form, therefore, present invention additionally comprises these optical isomers and its mixture.
The logical formula (I) compound of the present invention and its pharmaceutically acceptable salt and their stereoisomer can by oral administration, parenteral（Intravenous, intramuscular, subcutaneous or rectum etc.）, the administering mode such as transpulmonary, local be applied to mammal, such as people.The daily dose of the compounds of this invention can be about 0.05mg/kg body weight to about 0.5mg/kg weight ranges.
Formula (I) compound of the present invention or its pharmaceutically acceptable salt or their stereoisomer can constitute pharmaceutical composition with one or more pharmaceutical carriers.The composition can be prepared by the way that the logical formula (I) compound of the present invention or its pharmaceutically acceptable salt or their stereoisomer are mixed with one or more conventional pharmaceutical carriers and/or diluent.Described pharmaceutical composition can be configured to conventional formulation clinically use or pharmaceutically acceptable, and being applied in modes such as oral and parenteral administrations needs the patient of this treatment；Including but not limited to such as tablet, granule, glue Nang agent, pulvis, injection, inhalant, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, spray, preparation capable of permeating skin.These preparations can be added suitable pharmaceutical carrier such as conventional excipients, adhesive, humidizer, disintegrant, thickener etc. and be prepared from by conventional method.
Formula (I) compound of the present invention or its pharmaceutically acceptable salt or their stereoisomer can include but is not limited to other therapeutic agents administering drug combinations, the therapeutic agent：Angiotensin II antagonist or its pharmaceutically acceptable salt, including such as Losartan, Valsartan, Irbesartan, Olmesartan, Candesartan；HMG-Co-A reductase inhibitors or its pharmaceutically acceptable salt, including such as Lovastatin, Simvastatin, Pravastatin, mevastatin, Fluvastatin, Atorvastatin, cerivastatin, rosuvastatin；Aldosterone receptor antagonist（MRA) or its pharmaceutically acceptable salt, including such as spirolactone, eplerenone；Angiotensin converting enzyme/neutral endopeptidase（ACE/NEP) double inhibitor or its pharmaceutically acceptable salt, including for example Puli, thunder are stamped in captopril, alacepril, enalapril, lisinopril, training Meter Pu Li, quinapril, Delapril, Cilazapril, benazepil, Spirapril, Trandolapril, Moexipril, Imidapril, fosinopril etc.；Antidiabetic, including such as melbine, glibenclamide, Glipizide, Glibornuride, gliclazide, gliquidone, Xi Gelieting, vildagliptin, BMS-477118, the sour Egelietings of benzene Yue, Li Nalieting；Slimming drugs；Endothelin receptor antagonists, including such as Bosentan；CETP inhibitor；Na-K-ATP enzyme membrane pump inhibitors；B-adrenergic receptor inhibitor, including such as Betaloc, Carvedilol；α-Kidney upper parathyrine energy receptor blocking pharmacons, including such as prazosin, Terazosin, Doxazosin；Neutral endopeptidase（Ν Ε Ρ) inhibitor and inotropic agent etc..
It is demonstrated experimentally that the compounds of this invention has significant hypotensive activity, long-acting antihypertensive effect can be maintained, is preferable blood-pressure drug, and with L-type and the dual calcium channel retardation of Τ-type.Thus with heart, Renoprotective Effect, and ankle edema Small side effects.Therefore, formula (I) compound of the present invention and its pharmaceutically acceptable salt and their stereoisomer can be used in treatment/or prevention injury of kidney, cardiovascular and/or endocrine system disease, including hypertension, heart failure, miocardial infarction, angina pectoris, cardiomegaly, myocarditis, cardiovascular fibrosis, pressoreceptor dysfunction, excessive body fluid and cardiac arrhythmia, primary/secondary aldosteronism, Addison's disease, the emerging syndrome in storehouse and Bart's formula syndrome etc..
Compared with prior art, the compounds of this invention has advantages below：
(1) there are preferable hypotensive activity and Small side effects；
(2) there is excellent inhibitory activity to L-type and Τ-type calcium channel；
(3) good biological stability is shown, acts on more longlasting, bioavilability is high；
(4) preparation technology is simple, product purity height, high income, steady quality, it is easy to carry out large-scale industrial production.Embodiment
Below by way of specific embodiment, the present invention is described in further detail.But this should not be interpreted as the scope of the present invention and be only limitted to following examples.All technologies based on achieved by the above of the present invention belong to the scope of the present invention.
In embodiment, the representative implication of abbreviation is as follows： THF represents tetrahydrofuran
DMF represents dimethyl Yue acid amides
DIEA represents DIPEA
HATU represents 2- (7- azos BTA)-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester MsCl and represents p-methyl benzene sulfonic chloride
DCM represents dichloromethane embodiment
I. the preparation embodiment of the compounds of this invention
Embodiment 1:3- (1- benzyl -3- methylpyrrolidin- 3- bases）5- methyl 2,6- dimethyl -4- (3- nitrobenzophenones l, 4- dihydropyridine -3,5- dicarboxylic ester '（Compound 1) and its hydrochloride system
(1) preparation of 1- -3- methylpyrrolidin- 3- alcohol
Under -20 stir, 1- benzyl-pyrroles alkanone (1.1 g, 6.3mmol) is dissolved in 4 mL THF, and resulting solution is added drop-wise to Yue base magnesium bromides dropwise（13.2 mL, 12.2 mmol) THF solution in, continue stir 3 hours, reaction is finished, and reaction solution is dropped in water water, uses saturated common salt water washing, Na2S04After drying, through column chromatography for separation（Silicagel column, petroleum ether：Ethyl acetate=20:1 (volume ratio）Elution), 0.7 g product 1- benzyl -3- Yue base pyrrolidinyl -3- alcohol is obtained, yield is 58.1%.
The preparation of the Yue esters of bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic acids of (2) 2,6- two
By 5 g m-nitrobenzaldehydes (0.033 mol), 8 mL methyl acetoacetates (0.072 mol), 10 mL ethanol, 4 g ammonium hydrogen carbonate（0.05 mol) and the mixing of 4 mL water, in 55-60 °C of stirring to bubble-free（About 1 hour）, it is further continued for back flow reaction 1-2 hours, cools down, suction filtration is dry by filter cake vacuum thousand, obtains 8.1 g yellow solid title products, yield 70.9%.
(3) preparation of 5- Yue oxygen carbonyl -2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids
By 3.5g 2, 6- dimethyl -4- (3- nitrobenzophenones) -1, 4- dihydropyridines -3, 5- dimethyl dicarboxylates (0.01 mol) mix with 150 mL Yue alcohol, the lower saturated aqueous solution for adding 9 g NaOH (0.225 mol) of stirring, reaction 6 hours is stirred vigorously in 70 °C, decompression is steamed after 80 mL Yue alcohol, 200 mL water are added into residue, filter out unreacting material, filtrate is adjusted to about pH=2.5 with l mol/L hydrochloric acid, separate out yellow solid, filtering, dry, obtain khaki powder, handled with Yue alcohol, obtain 1.9 g yellow solid title products, yield 57.2%.
(4) the Yue bases -4- (3- nitrobenzophenones) of 5- Yue acyl groups -2,6- two -1,4- dihydropyridine -3- carboxylate methyl esters
Under -25 °C, thionyl chloride (0.4 g, 3.4 mmol) Slow is added drop-wise to the Yue bases -4- (3- nitrobenzophenones) -1 of 5- Yue oxygen carbonyls -2,6- bis- slowly, 4- dihydropyridine -3- carboxylic acids (1.0 g, 3 mmol) dichloro Yue alkane solution in, after completion of dropping, under ice cooling, 4 continue react to clarify, reaction is finished, by reaction solution rotary evaporated to dryness, crude product is obtained, continues next step reaction.
(5) preparation of 3- (1- benzyl -3- methylpyrrolidin- 3- yls) -5- methyl -2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic esters and its hydrochloride
Under -25 °C are stirred, by the Yue bases -4- (3- nitrobenzophenones) of 5- chlorine Yue acyl groups -2,6- bis- -1,4- dihydropyridine -3- carboxylic acid Yue esters（1.0 g, 2.85 mmol) it is added in the dichloro Yue alkane solution of 1- benzyl -3- methylpyrrole alkyl -3- alcohol (0.6 g, 3 mmol), after finishing, move to and continue to stir 12 hours at room temperature.Reaction is finished, by reaction solution rotary evaporated to dryness, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=10:1 (volume ratio）Elute) obtain compound 1.
Gained compound 1 is dissolved in dichloromethane, hydrogen chloride gas is passed through thereto, rotary evaporated to dryness obtains the hydrochloride of 0.4 g compounds 1, and yield is 25.9%.
Mass spectrum (M+H): 506.1
1H-NMR (CDC13, 400 MHz): δ 8.10 (IH, d);8.02 (1H, d); 7.64 (IH, m);7.40-7.34 (5H, m); 7.31-7.28 (IH, m); 5.65 (IH, s); 5.07 (IH, s);3.66 (3H, d); 3.65-3.52 (2H, m); 2.82 (2H, s);2.76-2.55 (2H, m), 2.38 (3H, s), 2.35 (3H, d), 2.24-2.22 (1H, m), 2.06-1.98 (IH, m), 1.50-1.46 (3H, d).Embodiment 2:3- " the 5- methyl 2 of l- (3,3- diphenylpropyl) -3- methylpyrrolidin- 3- bases 1,6- dimethyl
- 4--nitrobenzophenone) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Compound 2) and its salt
(1) preparation of the hydrochloride of 3- Yue bases pyrrolidines -3- alcohol
By 3- carbonyl pyrrolidine alkane -1- t-butyl formates (11.17 g, 0.06 mol) THF (45 mL) solution Slow be added to MeMgl (21.41 g slowly, 0.129 mol) diethyl ether solution in, in -20 °C of h of stirring reaction 3.A small amount of water is added in reaction solution, suction filtration, filtrate is extracted with dichloro Yue alkane, Organic layer anhydrous sodium sulfate drying, filtering, filtrate is concentrated, 3- hydroxy-3-methyls-pyrrolidines -1- carboxylate crude products are obtained.
Above-mentioned crude product is dissolved in 20 mL 1,4- dioxane（Dioxane), HC1 gases are passed through thereto, are stirred overnight, and suction filtration obtains 1.67 g red solid title products, and two step yields are 20%.
(2) preparation of 1- bases -1- ketone
The hydrochloride of 3- methylpyrrolidin- 3- alcohol is added in 100 mL eggplant-shape bottles（1.6 g, 11.6 mmol) 3,3- diphenyl-propionic acids（2.89 g, 12.9 mmol), DIEA (3.0 g, 23.3 mmol) and DMF (8 mL), stirred 15 minutes in 0 °C, then Slow adds HATU (4.86 g slowly, 12.8 mmol), stirring moves to room temperature after 10 minutes, is stirred overnight.Reaction solution is poured into water, is adjusted to about pH=6, is extracted with ethyl acetate with 10% watery hydrochloric acid, by organic phase anhydrous sodium sulfate drying, filtering, through column chromatography Pureization (silicagel column, petroleum ether after filtrate is evaporated：Ethyl acetate=15:1 (volume ratio））, obtain l.O g light red oil products, yield 28%.
(3)-(3,3- diphenylpropyls) preparation of -3- methylpyrrolidin- 3- alcohol
LiAlH is added in 250 mL eggplant-shape bottles4(0.36 g, 9.49 mmol) and THF (10 mL), stirred 15 minutes in -20 °C, Slow adds 1- (3- hydroxyl -3- Yue base pyrrolidines -1- bases) -3 slowly again, THF (5 mL) solution of 3- diphenylpropyl -1- ketone (1.0 g, 3.24 mmol), is finished, temperature rises to 70, continues to stir 4 h.It is cooled to room temperature, add 0.36 g water, 0.72 g 10% sodium hydroxide solution is added, 1.08 g water is eventually adding, then filters, filtrate is after being distilled off THF, extracted with dichloromethane, organic layer is washed with water and saturated common salt successively, filtered with after anhydrous sodium sulfate drying, filtrate is evaporated, lOO mg products are obtained；Dichloro Yue alkane is added into filter cake, filtrate is evaporated, obtains 550 mg products, altogether 650 mg, yield 68% by suction filtration after gained mixture is stirred. (4) 3- [l- (3,3- diphenylpropyl) -3- Yue bases pyrrolidin-3-yl] 5- methyl 2, the preparation of Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3, the 5- dicarboxylic esters of 6- bis- and its hydrochloride
1- (3 is added in 100 mL eggplant-shape bottles; 3- diphenylpropyls) -3- Yue base pyrrolidines -3- alcohol (0.65 g; 2.2 mmol), sodium acid carbonate (0.37 g; 4.4 mmol) and dichloro Yue alkane (4 mL); stirred 15 minutes in -25 °C; Slow adds 5- (chlorine Yue acyl groups) -2 slowly again; Yue bases-the 4- (3- nitrobenzophenones) -1 of 6- bis-; 4- dihydropyridine -3- carboxylic acid Yue esters (0.93 g; 2.64 mmol); stirring is warming up to 0 °C after 10 minutes, is stirred overnight.Filtering, through column chromatography for separation after filtrate is evaporated, obtains compound 2.
Gained compound 2 is dissolved in dichloro Yue alkane, HC1 gases are passed through thereto, after 10 minutes, filtering, by filtration cakes torrefaction, obtains the hydrochloride of 168 mg compounds 2, yield 11.4%.
Mass spectrum (M+H)： 610.2.Embodiment 3:3- (1- benzyl -3- methylpyrrolidin- 3- bases）5- ethyl 2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dihydropyridine -3,5- diester（Compound 3) preparation
Experimental procedure be the same as Example 1, but step（2) the reactant acetoacetate Yue esters in are replaced with ethyl acetoacetate, obtain compound 3.
Matter language (M+H)： 520.3.Embodiment 4:3- (1- (3,3- diphenylpropyl) -3- methylpyrrolidin- 3- bases）5- ethyl 2,6- dimethyl
- 4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester（Compound 4) preparation Reactant 5- (chloroformyl) -2,6- dimethyl in experimental procedure be the same as Example 2, but step (4) -4_(3_ nitrobenzophenone)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid Yue esters with 5- (chlorine Yue acyl groups) -2,6- dimethyl _ 4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid, ethyl esters replace, obtain compound 4.
Mass spectrum (M+H)： 624.2.Embodiment 5:3- (1- phenylpropyl -3- methylpyrrolidin- 3- bases）5- methyl 2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Compound 5) preparation
Experimental procedure be the same as Example 1, but step（1) the reactant 1- benzyl-pyrroles alkane -3- ketone in is replaced with 1- phenethyl pyrrolidines -3- ketone, obtains compound 5.
Mass spectrum (M+H)： 520.3.Embodiment 6:3- " the 5- methyl 2,6- dimethyl of 1- (2,2- Diphenethyls) -3- methylpyrrolidin- 3- bases 1
- 4- 3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Compound 6)
Experimental procedure be the same as Example 2, but step（2) reactant 3 in, 3- diphenyl-propionic acids are replaced with 2,2- diphenyl acetic acids, obtain compound 6.
Mass spectrum (M+H)： 596.2.Embodiment 3- (1- benzyl -3- Yue base pyrrolidin-3-yls）5- methyl 2- " (2- amino ethoxies) methyl 4- (2- chlorophenyls) -6- methyl isophthalic acids, 4- dihydropyridine -3,5- dicarboxylic esters（Compound 7) preparation 7
Experimental procedure be the same as Example 1, but step（2) the reactant m-nitro Yue aldehyde in is replaced with 2- chlorobenzaldehydes, obtains compound 7.
Matter Pass (M+H)： 554.3.Embodiment 8:3- Π-(3,3- diphenylpropyl) -3- methylpyrrolidin- 3- base 15- methyl 2- " (2- amino ethoxies) methyl 4- (2- chlorophenyls) -6- methyl isophthalic acids, 4- dihydropyridine -3,5- dicarboxylic acids
Experimental procedure be the same as Example 2, but step（4) 5- (chlorine Yue acyl groups in）- 2; Yue bases -4- (the 3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylate methyl esters of 6- bis- are with the Yue bases -4- (2- chlorphenyls) -1 of 5- (chloroformyl) -2,6- bis-; 4- dihydropyridine -3- carboxylate methyl esters are replaced, and obtain compound 8.
Mass spectrum (Μ+Η)： 658.2.Embodiment 9:3- Π-Yue the bases of 1 5- methyl 2,6- of (4- Fluoro-benz rLls) -3- Yue bases pyrrolidin-3-yl bis-
- 4- 3- nitrobenzophenones) -1,4- dihydropyridine -3,5- dicarboxylic acid esters（Compound 9)
Experimental procedure be the same as Example 1, but step（1) the reactant 1- benzyl-pyrroles alkane -3- ketone in is replaced with 1- (4- luorobenzyls) pyrrolidines -3- ketone, obtains compound 9. 12000577 matter i blinds (M+H)： 524.2.Embodiment 10:3- " the 4- 3- nitrobenzophenones of bis- Yue bases of 1- (4- Yue Gas bases benzyl) -3- methylpyrrolidin- 3- base 15- methyl 2,6- one) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Compound 10)
Experimental procedure be the same as Example 1, but step（1) the reactant 1- benzyl-pyrroles alkane -3- ketone in is replaced with 1- (4- Yue oxy-benzyls) pyrrolidines -3- ketone, obtains compound 10.
Matter i blinds (M+H)： 536.3.Embodiment 11:3-n-G, 3- bis- (4- difluorophenyls) propyl group) 1 5- methyl of -3- methylpyrrolidin- 3- bases
2,6- bis- Yue bases -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Change
Reactant 1- (3- hydroxyl -3- Yue bases pyrrolidin-1-yl) -3,3- diphenylpropyl -1- ketone in experimental procedure be the same as Example 2, but step (2) is with 1- (3,3- bis- (4- difluorophenyls）Propyl group) replacement of -3- Yue base pyrrolidines -3- ketone, obtain compound 11.
Mass spectrum (M+H)： 646.2.Embodiment 12:(4R) -3- (l- benzyl -3- Yue base pyrrolidin-3-yls）5- methyl 2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid ester hydrochlorides（Compound 12) preparation
(1) -5- methoxycarbonyl groups -2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids
To 5- Yue oxygen carbonyls -2,6- two Yue bases -4- (3- nitrobenzophenones) -1,4- dihydropyridine -3- carboxylic acids
The methanol of (700 g, 2.1 mol)（14 L) in solution, cinchonidine (617 g, 2.1 mol) is added, and in 90.C flows back, to being completely dissolved, and continues to stir 3 hours, adds 4.5 L water, continues to stir
0.5 hour, Slow cooled slowly, cooling, was settled out solid, filters, filter cake HCl treatment is obtained（S) Yue bases-the 4- (3- nitrobenzophenones) of -5- (Yue oxygen carbonyls) -2,6- bis- -1,4- dihydropyridine -3- carboxylic acids (130 g), the % of yield 18.6.
(2) preparation of (R) -5- chloroformyl -2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dihydropyridine -3- carboxylic acid Yue esters
Under -25 °C, by thionyl chloride (0.4 g, 3.4 mmol) Slow is added drop-wise to 5- methoxycarbonyl groups -2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids (1.0 g slowly, 3 mmol) dichloro Yue alkane solution in, after completion of dropping, reacted in the lower continuation of ice bath cooling to clarifying, reaction is finished, by reaction solution rotary evaporated to dryness, continue next step reaction.
(3) (4R) -3- (l- benzyl -3- methylpyrrolidin- 3- bases）5- Yue bases 2, the preparation of 6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester hydrochloride
Under -25 °C, by 5- chloroformyls -2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acid Yue esters（1.0 g, 2.85 mmol) it is added drop-wise in the dichloro Yue alkane solution of 1- benzyl -3- methylpyrrolidin- 3- alcohol (0.6 g, 3 mmol), after completion of dropping, move to and continue to stir 12 hours at room temperature.Reaction is finished, by reaction solution rotary evaporated to dryness, through column chromatography for separation (silicagel column, V (petroleum ether):V (ethyl acetate)=10:1) solid is obtained, is dissolved in dichloro Yue alkane, hydrogen chloride gas is passed through thereto, by gained mixture rotary evaporated to dryness, 0.4 g target products are obtained, yield is 27.8 %.Embodiment 13:(4S) -3- (l- benzyl -3- methylpyrrolidin- 3- bases）- 3,5- the dicarboxylic esters of 5- methyl 2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- two（Compound 13) preparation
Experimental procedure be the same as Example 12, but step（3) C5 in) bis- Yue bases -4- of -5- Yue oxygen carbonyls -2,6-（3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine-3- carboxylic acids with Yue bases-4- (the 3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine-3- carboxylic acids of 00-5- methoxycarbonyl groups-2,6- bis- replace.
(R) step of preparation method reference implementation example 15 of-5-Yue oxygen carbonyl-2,6- dimethyl-4- (3-nitrobenzophenone)-Isosorbide-5-Nitrae-dihydropyridine-3- carboxylic acids（ 1 ) .Embodiment 14:(4R) -3- " the 5- methyl 2 of l- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- bases 1,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester（Compound 14) preparation
Experimental procedure be the same as Example 15, but step（5) (- 5- methoxycarbonyl groups -2 in, Yue bases-the 4- (3- nitrobenzophenones) -1 of 6- bis-, 4- dihydropyridine -3- carboxylic acids are with 0S) -5- Yue oxygen carbonyl -2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dihydropyridine -3- carboxylic acids replacement.
(7) -5- Yue oxygen carbonyls -2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids the step of preparation method reference implementation example 12（1 ).Embodiment 15:(4S) -3- " the 5- methyl 2 of l- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- bases 1,6- dimethyl _ 4- (3- nitrobenzophenones l, 4- dihydropyridine -3,5- dicarboxylic ester（Compound 15) preparation
(1) system of (R) -5- (Yue oxygen carbonyls) -2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids
To 5- (methoxycarbonyl group) -2, Yue bases-the 4- (3- nitrobenzophenones) -1 of 6- bis-, 4- dihydropyridine -3- carboxylic acids (700 g, 2.1 mol) methanol (14 L) solution in, add quinindium (Quinidine) (617 g, 1, 90 mol), and in 90 °C of backflows, to being completely dissolved, continue to stir 3 hours, add 4.5 L water, continue to stir 0.5 hour, Slow cools slowly, cooling, it is settled out solid, filtering, by filter cake HCl treatment, obtain (R) -5- (Yue oxygen carbonyls) -2, Yue bases-the 4- (3- nitrobenzophenones) -1 of 6- bis-, 4- dihydropyridine -3- carboxylic acids (130 g), the % of yield 18.6.
(2) preparation of 3- hydroxyls -3- Yue bases -1- carboxylates
Under -10 °C, the dry THF of 4 L thousand are added into 30 L reactor, are stirred, ZnCl is added2(1 (402 9.5 11101), after 0.5 hour, MeMgBr (3 is added dropwise in Slow slowly by (118 0.86 11101) and 1^ Mol/L diethyl ether solution (6.4 L), 19.2 mol), continue to stir 0.5 hour, 3- oxo-pyrrolidine -1- carboxylates (1600 g are added dropwise in Slow slowly, 8.6 mol) THF solution, after HPLC detection reactions completely, saturation NH is added dropwise into system4Reaction is quenched in C1 solution, is extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, and solvent is evaporated off and obtains the faint yellow solid small carboxylate of shape 3- hydroxy-3-methyl pyrrolidines (1450 g), the % of yield 83.8.
(3) preparation of 3- Yue bases pyrroles -3- alcohol hydrochlorides
Under ice bath cooling, into 10 L there-necked flask, 5 L Isosorbide-5-Nitraes-dioxane and the 3- small carboxylates of hydroxyl -3- crassitudes (1450 g are added, 7.2 mol), 2.2 L HC1/ ethanol solutions (30 %) are added dropwise in stirring, Slow slowly, finish and are reacted 12 hours after 25 °C, TLC monitoring reactions are finished, suction filtration, obtains red brown solid shape 3- Yue base pyrrolidines -3- alcohol hydrochlorides (750 g), the % of yield 75.6.
The preparation of (4) 3,3- diphenyl -1- propyl alcohol
Under -20 °C, into 30 L reactor, Slow adds the Yue benzole solns of 15 L diisobutyl aluminium hydrides slowly（1 moL/L), stirring, Slow is added dropwise 3 slowly, the small ethyl propionate of 3- diphenyl (1200 g, 4.7 mol) dichloromethane solution, completion of dropping is reacted 12 hours after 25 °C, and TLC monitoring reactions are complete, and reaction solution is divided into three parts, under -20 °C, Slow adds 200 mL Yue alcohol slowly respectively and 1000 mL water are quenched, and merges, and is extracted with dichloro Yue alkane, organic phase is through anhydrous sodium sulfate drying, solvent is evaporated off and obtains oily 3, the small propyl alcohol crude product of 3- diphenyl (1000 g) is directly used in next step reaction.
(5) preparation of 3,3- diphenyl propyls Yue sulphonic acid esters
3,3- diphenyl -1- propyl alcohol (1000 g, 4.7 mol) is dissolved in 3L dichloromethane, add under triethylamine (712 g, 7.05 mol), 0 °C, stirring 0.5 hour, MsCl (645 g, 5.64 mol) is added dropwise in Slow slowly, in 25 °C of reactions, TLC monitoring reactions finish, reaction solution are washed with water three times, organic phase is evaporated off solvent and obtains oily crude product, isopropanol is added into the crude product through anhydrous sodium sulfate drying, suction filtration 1000 g 3 are obtained, 3- diphenyl propyl Yue sulphonic acid ester solids add up to the % of two step yield 73.
(6) 1- (preparations of 3,3- diphenyl -3- Yue base pyrrolidines -3- alcohol
Into 10 L reaction bulb, add 3- methylpyrrolidin- 3- alcohol hydrochlorides (616 g, 4.48 mol), without sour clock (1186 g of 7j ^, 8.6 mol) and the L of acetonitrile 5,85 °C of lower Slow are added dropwise 3 slowly, 3- diphenyl propyl Yue sulphonic acid esters (1000 g, 3.45 mol) acetonitrile solution, react 12 hours, TLC monitoring reactions are complete, remove acetonitrile under reduced pressure, the mixed liquor extraction point liquid of dichloromethane and water is added, organic phase anhydrous sodium sulfate drying is evaporated off solvent and obtains crude product, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=50: 1
(volume ratio)) obtain 1- (3,3- diphenyl propyl) -3- Yue base pyrrolidines -3- alcohol (580 g), the % of yield 57.
(7) (4 3- [1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- yls] 5- methyl 2, the preparation of 6- dimethyl -4- (3- nitrobenzophenones) -1,4- dihydropyridine -3,5- dicarboxylic esters
To (R) -5- methoxycarbonyl groups -2, 6- dimethyl -4- (3- nitrobenzophenones) -1, 4- dihydropyridine -3- carboxylic acids (67.5 g, 0.2 mol) dichloromethane solution in add 1, 5 mL DMF, Slow instills oxalyl chloride (51 g slowly under water-bath, 0.4 mol), in 25 °C of reactions, until reaction is complete, remove oxalyl chloride under reduced pressure, under ice cooling, 4 respectively by the mL of dichloromethane 300, 1- (3, 3- diphenyl propyls) -3- Yue base pyrrolidines -3- alcohol (29.5 g, 0.1 mol) and DIPEA (25.8 g, 0.2 mol) successively Slow be added dropwise to slowly in reaction bulb, in 25 °C of reactions, HPLC monitorings are complete until reaction, reaction solution is washed with water three times, organic phase is dried over sodium sulfate, suction filtration, filtrate is evaporated, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=80:1 (volume ratio））, obtain (4S) -3- [l- (3,3- diphenyl propyl) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2, Yue bases-the 4- (3- nitrobenzophenones) -1 of 6- bis-, 4- dihydropyridines -3,5- dicarboxylic ester (34 g), the % of yield 56.Embodiment 16:(S) -3-fiS) -3,3- diphenyl propyls) 1 5- methyl of -3- methylpyrrolidin- 3- bases
2,6- bis- Yue bases -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Change Compound 16)
(1) preparation of (5) small (3,3- diphenyl propyls) -3- Yue base pyrrolidines -3- alcohol
(+) -Di-l,4-toluoyl-D
-tartaric acid . NaOH
According to embodiment 15, synthesize (R) -5- (methoxy shallow lake overgrown with wild plants base) -2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids and 1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- alcohol.Under 90 °C, to D- bis- (to toluyl) tartaric acid（（+)-Di-l, 4-toluoyl-D-tartaric acid) (280 g, 0.7 mol) isopropanol (300 mL) solution in add 1- (3,3- diphenyl propyls) -3- Yue base pyrrolidines -3- alcohol (280 g, 0.95 mol) isopropanol (300 mL) solution, 30 °C are cooled to slowly after Slow after solution clarification, filtering, obtain white solid, naoh treatment obtains (5) -1- (3,3- diphenyl propyls) -3- Yue base pyrrolidines -3- alcohol (52 g), the % of yield 18.6.
(2) (5) -3- [(5) small (3,3- diphenyl propyl) -3- Yue bases pyrrolidin-3-yl] 5- methyl 2, the 6- dimethyl -4- (preparations of 3- nitre-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic esters
According to embodiment 15, (R) -5- Yue oxygen shallow lake overgrown with wild plants base -2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dihydropyridine -3- carboxylic acids are synthesized.To (7-5- methoxycarbonyl groups-2,6- dimethyl-4- (3- nitrobenzophenones)-1,4- dihydropyridine-3- carboxylic acids (33.75 g, 0.1 mol) dichloromethane solution in add 1 mL DMF, the lower Slow of ice bath cooling instills oxalyl chloride (25.5 ^ 0.2 11101) slowly, in 25 °C of reactions, until reaction is complete, remove oxalyl chloride under reduced pressure, under ice bath cooling respectively by the mL of dichloromethane 200,（6) -1- (3,3- diphenyl propyls) -3- methylpyrrolidin- 3- alcohol (14.75 g, 0.05 mol) and DIPEA (12.9 g, 0.1 mol) Slow is added dropwise in reaction bulb slowly successively, in 25 °C reaction, HPLC monitorings are complete until reaction, reaction solution is washed with water three times, organic phase is through anhydrous sodium sulfate drying, suction filtration, filtrate is evaporated, through column chromatography for separation (silicon Glue post, petroleum ether：Ethyl acetate=80:1 (volume ratio））Obtaining title product, ([() is small by (3 by 5 3-, 3- diphenyl propyls) -3- methyl -3- pyrrolidinyls] 5- methyl 2, Yue bases-the 4- (3- nitrobenzophenones) -1 of 6- bis-, 4- dihydropyridines -3,5- dicarboxylic esters (17 g), the % of yield 56, it is+98 ° ~+118 ° (temperature to measure the optical activity scope of four batches of Product samples：20, concentration：2 mg/mL, MeOH dissolve), wherein the optical activity of a collection of sample is+108.34..Test sample compound 16 in following pharmacological experimental examples is the sample that optical activity is+108.34 °.
Molecular formula： C36H39N306Molecular weight：609.2 mass spectrums (M+H): 610.3 ^-NMRCDMSO, 400 MHz) ό:9.13-9.11 (1 H, d), 8.05-7.94 (2 Η, m), 7.61-7.49 (2 Η, m), 7.33-7.27 (8 Η, m), 7.20-7.17 (2 Η, m), 4.93-4.88 (1 Η, d), 4.00-3.95 (1 Η, m), 3.95-3.53 (1 Η, m), 3.53-3.52 (3 Η, d), 3.13 (2 Η, m), 2.84-2.83 (4 Η, m), 2.42-2.36 (3 Η, m), 2.27-2.21 (6 Η, m), 2.23-2.21 (1 Η, m), 1.49-1.41 (3 H, d).Embodiment 17:(S) -3- " (R) -3,3- diphenyl propyls) 1 5- methyl of -3- methylpyrrolidin- 3- bases
2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Compound 17) preparation
(l) ( ) small-diphenyl propyl) and -3- methylpyrrolidin- 3- alcohol preparation
According to embodiment 15, synthesis (R) -5- (Yue oxygen betray base) -2, Yue bases -4- (the 3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids of 6- bis- and 1- (3,3- diphenyl propyl) -3- methylpyrrolidin- 3- alcohol.
By after the compound and L- bis- (to Yue base benzene Yue acyls) tartaric acid, then obtain with NaOH processing product i.e. (small (3,3- the diphenyl propyl) -3- methylpyrrolidin- 3- alcohol of R configurations.
(2) (5 3-[(/) small (3,3- diphenyl propyl) -3- Yue bases pyrrolidin-3-yl] 5- methyl 2, the preparation of 6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester
According to embodiment 16, synthesize (5 3- |) -1- (3,3- diphenyl propyls) -3- Yue base pyrrolidines -3- bases] 5- methyl 2, Yue bases-the 4- (3- nitrobenzophenones) -1 of 6- bis-, 4- dihydropyridines -3,5- dicarboxylic esters, reactant () is small by (3,3- diphenyl propyls) -3- Yue base pyrrolidines -3- alcohol replace with it is (small by (3,3- diphenyl propyls) -3- Yue base pyrrolidines -3- alcohol, the % of yield 45, optical activity is+36.4 ° of (temperature：20 °C, concentration：2 mg/mL, MeOH dissolve).Embodiment 18:(4S) -3- " the 5- methyl 2 of l- (2,2- diphenyl-ethyl) -3- Yue bases pyrrolidin-3-yl 1,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester（Compound
(1) 2,2- diphenyl acetic acids
In 500 mL there-necked flask, add 2, 2- diphenyl acetic acids (20 g, 94 mmol) and 200 mL dichloromethane, stirring, add 1 mL DMF, Slow instills oxalyl chloride (13.16 g slowly under ice bath, 104 mmol), in 25 °C of reactions, until reaction is complete, remove oxalyl chloride under reduced pressure, respectively by 100 mL dichloromethanes protective embankments and absolute methanol (3.61 g under water-bath cooling, 113 mmol) Slow is added dropwise in reaction bulb slowly, in 25 °C of reactions, until reaction is complete, reaction solution is washed with saturated common salt, organic phase is dried with sodium sulphate, suction filtration, filtrate is evaporated, obtain 2, 2- diphenyl acetic acids methyl esters (21 g), the % of yield 98.7.
(2) preparation of 2,2- diphenyl ethanol
Under -30 °C, into 500 mL there-necked flask, Slow adds the toluene of diisobutyl aluminium hydride slowly（282 mL) solution (1 moL/L), stirring, Slow is added dropwise 2 slowly, 2- diphenyl acetic acid Yue esters (21 g, 92.8 mmol) dichloromethane solution, completion of dropping reacts 12 hours after 25 °C, and TLC monitoring reactions are complete, under -20 °C, Slow adds 10 mL methanol, 100 mL dichloromethane and 100 mL sodium hydrate aqueous solutions slowly（I moL/L), after reaction terminates, reaction solution adds dichloro Yue alkane and extracted, and organic phase is washed with water, anhydrous sodium sulfate drying, and solvent is evaporated off, and obtains 2,2- diphenyl ethanol (17 g), the % of yield 92.4.
(3) 2,2- diphenyl-ethyls Yue sulphurs
In 500 mL there-necked flask, by 2,2- diphenyl ethanol (17 g, 86 mmol) it is dissolved in 170 mL dichloromethane, triethylamine (13.03 g, 129 mmol) is added, is stirred 0.5 hour in 0 °C, MsCl (11.92 g are added dropwise in Slow slowly, 104 mmol), in 25 °C of reactions, TLC monitoring reactions are finished, reaction solution is washed three times, organic phase anhydrous sodium sulfate drying, is evaporated off solvent, obtains 2,2- diphenyl-ethyls methanesulfonates (23 g), the % of yield 96.78.
(4) 1- (preparations of 2,2- diphenyl-ethyl -3- methylpyrrolidin- 3- alcohol
According to embodiment 15,3- Yue base pyrrolidines -3- alcohol hydrochlorides are synthesized.In 500 mL reaction bulb, add 3- methylpyrrolidin- 3- alcohol hydrochlorides (11.46 g, 83 mmol), Anhydrous potassium carbonate (28.75 g, 208 mmol) and the mL of acetonitrile 220, 85 °C of lower Slow are added dropwise 2 slowly, 2- diphenyl-ethyl Yue sulphonic acid esters (23 g, 83 mmol) acetonitrile solution, reaction 12 hours, TLC monitoring reactions are complete, remove acetonitrile under reduced pressure, add the mixed liquor extraction point liquid of dichloro Yue alkane and water, talented mesh anhydrous sodium sulfate drying, solvent is evaporated off and obtains crude product, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=30:1 (volume ratio））, obtain 1- (2,2- diphenyl-ethyl) -3- Yue base pyrrolidines -3- alcohol (13.6 g), the % of yield 58.23. (5) (45) -3- [l- (2,2- diphenyl-ethyl) -3- methylpyrrolidin- 3- yls] 5- Yue bases 2, the preparation of the Yue bases of 6- bis- _ 4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester
According to embodiment 15, Yue bases -4- (the 3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids of synthesis (R) -5- Yue oxygen carbonyls -2,6- bis-.To (R) -5- methoxycarbonyl groups -2, Yue bases-the 4- (3- nitrobenzophenones) -1 of 6- bis-, 4- dihydropyridine -3- carboxylic acids (17.67 g, 53 mmol) dichloro Yue alkane solution in add 1 mL DMF, the lower Slow of water-bath cooling instills oxalyl chloride (8.1 g slowly, 64 mmol), in 25 °C of reactions, until reaction is complete, remove oxalyl chloride under reduced pressure, respectively by 120 mL dichloromethane under water-bath cooling, 1-(2, 2- diphenyl-ethyls) -3- methylpyrrolidin- 3- alcohol (13.6 g, 48 mmol) and DIPEA (12.38 g, 96 mmol) successively Slow be added dropwise to slowly in reaction bulb, in 25 °C of reactions, HPLC monitorings are complete until reaction, reaction solution is washed with water three times, organic phase is dried with sodium sulphate, suction filtration, filtrate is evaporated, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=70:1 (volume ratio））, obtain（4S) -3- [l- (2,2- diphenyl-ethyls) -3- Yue bases pyrrolidin-3-yl] 5- methyl 2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic esters (14.58 g), the % of yield 51.
Molecular formula： C35H37N306Molecular weight：595.2 mass spectrums (M+H): 596.3
^-NMRCDMSO, 400 MHz) and δ 9.16 (1 H, s), 7.99-7.91 (2 Η, m), 7.57-7.51 (2 Η, m), 7.49-7.34 (8 Η, m), 7.32-7.23 (2 Η, m), 4.89-4.83 (1 Η, d), 4.52 (1 Η, s), 3.96-3.53 (2 Η, m), 3.52-3.33 (5 Η, m), 3.26-3.23 (2 H, m), 2.26-2.23 (7 H, m), 1.98-1.91 (1H, m), 1.42-1.26 (3 H, m).Embodiment 19:(S) -3- " the 5- methyl of (R/S)-l- (2,2- diphenyl-ethyl) -3- methylpyrrolidin- 3- bases 1
2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Compound 19 and compound 20) preparation
Entrust Daicel medicine chiral technology（Shanghai）Co., Ltd uses HPLC methods to carry out chiral isomer separation to compound 18 with Daicel chiral column, collects its respective components, and rotary evaporation removes solvent, obtains the sterling of optical isomer：Compound 19 and compound 20.Separation condition difference is as follows：
Compound 19:
Chiral column type number（Column )： CHIRALCEL OD-H
Chiral column specification (Column size)： 0.46 cm I.D. x 15 cm L
Mobile phase（ Mobile phase )： C02/ MeOH I DEA=80/20/ 0.1 (V/V/V) Detection wavelength（ Wave length )： UV 220 nm
Column temperature（Temperature )： 35 °C
Retention time（Retention Time )：7.333 minute；
And
Compound 20:
Chiral column type number（Column )： CHIRALCEL OD-H
Chiral column specification (Column size)： 0.46 cm I.D. x 15 cm L
Mobile phase（ Mobile phase )： C02/ MeOH I DEA=80/20/ 0.1 (V/V/V) Detection wavelength（ Wave length )： UV 220 nm
Column temperature（Temperature )： 35 .C
Retention time（ Retention Time )：8.493 minute.
Angle-of-rotation measuring：
Compound 19:DMSO dissolves, and concentration is 20mg/ml, and temperature is 20 °C, measures optically-active luminosity for -3.7 °;
Compound 20:DMSO dissolves, and concentration is 20mg/ml, and temperature is 20 °C, and it is+35.2 to measure optically-active luminosity.. Embodiment 20:The 5- methyl 2 of (4S) -343- Yue bases-l- (3- phenylpropyls) pyrrolidin-3-yl 1,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester（Compound 21) preparation
(1) small (3- phenylpropyls) pyrroles of 3- methyl washes the preparation of -3- alcohol
According to embodiment 15,3- methylpyrrolidin- 3- alcohol hydrochlorides are synthesized.Into 100 mL reaction bulb, add 3- Yue base pyrrolidines -3- alcohol hydrochlorides (1 g, 7.2 mmol), Carbon Dioxide clock (2.5 g, 18 mmol) and the mL of acetonitrile 15, 3- bromopropyls benzene (1.29 g are added dropwise slowly in 85 °C of Slow, 6.48 mmol) 0 acetonitrile solution, reaction 12 hours, TLC monitoring reactions are complete, remove acetonitrile under reduced pressure, the mixed liquor extraction point liquid of dichloro Yue protective embankments and water is added into residue, organic phase anhydrous sodium sulfate drying, solvent is evaporated off and obtains crude product, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=10:1 (volume ratio））Obtain small (3- phenylpropyls) pyrrolidines -3- alcohol (1 g) of 3- Yue bases, the % of yield 70.4.
(2) (S) -3- [3- methyl isophthalic acids-(3- phenylpropyl) Bi Ka Stand-for-sacrifice -3- bases] 5- methyl 2, the preparation of 6- dimethyl -4- (3- nitrobenzophenones) -1,4- dihydropyridine -3,5- dicarboxylic esters
According to embodiment 15, synthesis (R) -5- Yue oxygen is betrayed base -2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids.To (R) -5- methoxycarbonyl groups -2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dihydropyridine -3- carboxylic acids (2.72 g, 8.18 mmol) dichloromethane solution in add 0.1 mL DMF, the lower Slow of ice bath cooling instills oxalyl chloride (2.08 g slowly, 16.39 mmol), in 25 °C of reactions, until reaction is complete, oxalyl chloride is removed under reduced pressure, respectively by dichloro Yue alkane 20 mL, 3- methyl isophthalic acid-(3- phenylpropyls) under ice bath cooling Pyrrolidines -3- alcohol (1 g, 4.56 mmol) and DIPEA (1.46 g, 11.30 mmol) successively Slow be added dropwise to slowly in reaction bulb, in 25 °C of reactions, HPLC monitorings are complete until reaction, reaction solution is washed with water three times, organic phase is dried with sodium sulphate, suction filtration, and filtrate is evaporated, through column chromatography for separation (silicagel column, petroleum ether:Ethyl acetate=87:1 (volume ratio））Obtain (4S) -3- [small (3- phenylpropyls) pyrrolidinyl -3- bases of 3- Yue bases] 5- Yue bases 2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic esters (1.15 g), the % of yield 47.3.
Molecular formula： C3。H35N306Molecular weight:533.2 mass spectrums (M+H):534.3 ^-NMRCDMSO, 400 MHz) and δ 9.20-9.17 (1 H, d), 9.16-7.97 (2 Η, m), 7.63-7.53 (2 Η, m), 7.30-7.19 (5 Η, m), 4.95-4.91 (1 Η, m), 3.56-3.55 (1 Η, m):3.54-3.41 (4 Η, m), 3.40-3.15 (1 Η, m), 3.12-3.07 (4 H, m), 2.61-2.49 (2 H, m), 2.29 (6 H, s), 1.96-1.90 (2H, m), 1.52-1.36 (3 H, dd), 1.10-1.03 (2 H, m).Embodiment 2U (4S) -3- (3- Yue base -1- phenethyl pyrrolidin-3-yls）5- methyl 2, the Yue bases of 6- bis-
- 4- 3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Compound 22)
(1) preparation of 3- methyl isophthalic acids-benzene second pyrrolidines -3- alcohol
According to embodiment 15,3- Yue base pyrrolidines -3- alcohol hydrochlorides are synthesized.Into 100 mL anti-bottle, add 3- methylpyrrolidin- 3- alcohol hydrochlorides (1 g, 7.2 mmol), Carbon Dioxide clock (2.5 g, 18 mmol) and the mL of acetonitrile 15,2 bromoethyl benzene (1.2 g are added dropwise slowly in 85 °C of Slow, 6.48 mmol) acetonitrile solution, react 12 hours, TLC monitoring reactions are complete, remove acetonitrile under reduced pressure, the mixed liquor extraction point liquid of dichloro Yue alkane and water is added into residue, organic phase anhydrous sodium sulfate drying is evaporated off solvent and obtains crude product, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=30:1 (volume ratio））, Obtain 3- methyl isophthalic acids-phenethyl pyrrolidines -3- alcohol (1 g), the % of yield 75,2.
(2) (45) -3- (3- methyl isophthalic acids-phenethyl pyrrolidin-3-yl）The preparation of the Yue bases -4- (3- nitrobenzophenones) of 5- Yue bases 2,6- bis- -1,4- dihydropyridine -3,5- dicarboxylic esters
According to embodiment 15, Yue bases -4- (the 3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids of synthesis (R) -5- Yue oxygen carbonyls -2,6- bis-.To (R) -5- methoxycarbonyl groups -2, 6- dimethyl -4- (3- nitrobenzophenones) -1, 4- dihydropyridine -3- carboxylic acids (2.9 g, 8.73 mmol) dichloro Yue alkane solution in add 0.1 mL DMF, Slow instills oxalyl chloride (2.2 g slowly under ice bath, 17.33 mmol), in 25 °C of reactions, until reaction is complete, remove oxalyl chloride under reduced pressure, respectively by the mL of dichloromethane 20 under ice bath cooling, 3- Yue base -1- phenethyl pyrrolidines -3- alcohol (1 g, 4.87 mmol) and DIPEA (1.56 g, 12.1 mmol) successively Slow be added dropwise to slowly in reaction bulb, in 25 °C of reactions, HPLC monitorings are complete until reaction, reaction solution is washed with water three times, organic phase is dried with sodium sulphate, suction filtration, filtrate is evaporated, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=78:1 (volume ratio））, obtain (S) -3- (small phenethyl pyrrolidin-3-yls of 3- Yue bases）5- Yue bases 2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester (1.21 g), the % of yield 48.
Molecular formula： C29H33N306Molecular weight：519.2 shields compose (M+H): 520.3 ^-NMRCDMSO, 400 MHz) δ:9.20-9.18 (1 H, d), 8.03-7.97 (2 Η, m), 7.64-7.53 (2 Η, m), 7.34-7.21 (5 Η, m), 4.96-4.93 (1 Η, d), 3.56-3.54 (2 Η, m), 3.52-3.41 (3 Η, m), 3.34-3.17 (1 Η, m), 3.07-2.93 (2 H, m), 2.50-2.49 (2 H, m), 2.31-2.29 (6 H, d), 2.26 (lH, m), 1.54-1.39 (3 H, dd), 1.1 (1 H, s), 1.05 (1 H, t).Embodiment 22:(4SV3- " the 5- methyl 2 of l- (3,5- difluorobenzyl) -3- methylpyrrolidin- 3- bases 1,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester（Compound 23) preparation
(1) l- (preparations of 3,5- difluorobenzyl -3- Yue base pyrrolidines -3- alcohol
According to embodiment 15,3- Yue base pyrrolidines -3- alcohol hydrochlorides are synthesized.Into 100 mL reaction bulb, add 3- Yue base pyrrolidines -3- alcohol hydrochlorides (1 g, 7.2 mmol), Anhydrous potassium carbonate (2.5 g, 18 mmol) and the mL of acetonitrile 15, 3 are added dropwise slowly in 85 °C of Slow, the fluorobenzyl bromides of 5- bis- (1.64 g, 7.9 mmol) acetonitrile solution, reaction 12 hours, TLC monitoring reactions are complete, remove acetonitrile under reduced pressure, the mixed liquor extraction point liquid of dichloro Yue alkane and water is added into residue, there is mesh anhydrous sodium sulfate drying, solvent is evaporated off and obtains 1- (3, 5- difluorobenzyls) -3- Yue base pyrrolidines -3- alcohol crude products (1.8 g), it is directly used in next step.(2) (S) -3- [l- (3,5- difluorobenzyl) -3- methylpyrrolidin- 3- yls] 5- methyl 2, the preparation of 6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester
According to embodiment 15, Yue bases -4- (the 3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids of synthesis (R) -5- methoxycarbonyl groups -2,6- bis-.To (R) -5- methoxycarbonyl groups -2, Yue bases-the 4- (3- nitrobenzophenones) -1 of 6- bis-, 4- dihydropyridine -3- carboxylic acids (4.86 g, 14.6 mmol) dichloro Yue alkane solution in add 0.1 mL DMF, Slow instills oxalyl chloride (3.68 g slowly under ice bath, 29.0 mmol), in 25 °C of reactions, until reaction is complete, remove oxalyl chloride under reduced pressure, respectively by the mL of dichloro Yue alkane 20 under ice bath cooling, 1- (3, 5- difluorobenzyls) -3- methylpyrrolidin- 3- alcohol crude products (1.8 g) and DIPEA (1.86 g, 14.4 mmol) successively Slow be added dropwise to slowly in reaction bulb, in 25 °C of reactions, HPLC monitorings are complete until reaction, reaction solution is washed with water three times, organic phase is dried with sodium sulphate, suction filtration, filtrate is evaporated, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=85:1 (volume ratio））, obtain (4S) -3- [l- (3,5- difluorobenzyl) -3- Yue base -3- pyrrolidines -3- Base] 5- Yue base 2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acids esters (1.78 g), add up to the % of two-step reaction yield 45.6.
Molecular formula: C28H29F2N306Molecular weight:541.2 mass spectrums (M+H): 543.3 ^-NMRCDMSO, 400 MHz) δ:9.14 (1 H, t), 8.02-7.97 (2 Η, m),
7.60-7.55 (2 Η, m), 7.39-7.33 (2 Η, m), 4.93-4.90 (1 Η, d), 4.41-4.40 (2 Η, m),
3.56-3.53 (6 Η, m), 3.35 (1 Η, s), 3.07 (1 Η, s), 2.30-2.26 (6 Η, m), 1.50-1.24
(3 Η, dd), 1.10 (3 Η, s).Embodiment 23:The 5- methyl 2,6- dimethyl of (4S) -3-ri- benzhydryl -3- methylpyrrolidin- 3- bases 1
- 4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Compound 26) preparation
(1) -5- (Yue oxygen carbonyls) -2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3- carboxylic acids
To 5- (Yue oxygen carbonyls) -2,6- two Yue bases -4- (3- nitrobenzophenones) -1,4- dihydropyridine -3- carboxylic acids
The methanol of (700 g, 2.1 mol)（14 L) in solution, add quinindium (Quinidine) (617 g, 1.90 mol), and in 90 °C of backflows, to being completely dissolved, continue to stir 3 hours, 4.5 L water are added, continue to stir 0.5 hour, Slow cools slowly, cooling, is settled out solid, filters, by filter cake HCl treatment, obtain the Yue bases -4- (3- nitrobenzophenones) of (R) -5- (methoxycarbonyl group) -2,6- bis--Isosorbide-5-Nitrae-dihydropyridine
- 3- carboxylic acids (130 g), the % of yield 18.6.
The preparation of-Yue-1-carboxylates of base of (2) 3-hydroxyl-3 Under -10 °C, the THF of 4 L dryings is added into 30 L reactor, stirring adds ZnCl2(118 g, 0.86 mol) and LiCl (402 g, 9.5 mol), after 0.5 hour, MeMgBr (3 mol/L) diethyl ether solution (6.4 L are added dropwise in Slow slowly, 19.2 mol), continue to stir 0.5 hour, 3- oxo-pyrrolidine -1- carboxylates are added dropwise in Slow slowly（1600 g, 8.6 mol) THF solution, after HPLC detection reactions completely, saturation NH is added dropwise into system4Reaction is quenched in C1 solution, it is extracted with ethyl acetate, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying and solvent is evaporated off, obtains the 3- hydroxyl small carboxylates of -3- Yue base pyrrolidines (1450 g), for faint yellow solid, the % of yield 83.8.
(3) preparation of 3- methylpyrroles -3- alcohol hydrochlorides
Under ice bath, into 10 L there-necked flask, Isosorbide-5-Nitrae-dioxane is added（5 L) and the small carboxylate of 3- hydroxy-3-methyl pyrrolidines（145 (^, 7.2 11101), HC1/ ethanol solutions (30 %, 2.2 L) are added dropwise in stirring, Slow slowly, finish and reacted 12 hours after 25 °C, TLC monitoring reactions are finished, and suction filtration obtains 3- methylpyrrolidin- 3- alcohol hydrochlorides (750 g), for red brown solid, the % of yield 75.6.
(4) preparation of 1- (benzhydryl) -3- -3- alcohol
Into reaction bulb, 3- Yue base pyrrolidines -3- alcohol hydrochlorides are added（1 g, 7.2 mmol), Anhydrous potassium carbonate (2.5 g, 18 mmol) and the L of acetonitrile 50, diphenyl-bromomethane is added dropwise slowly in 85 °C of Slow（1.78 g, 7.2 mmol) acetonitrile solution, reaction 12 hours, TLC monitoring reactions are complete, remove acetonitrile under reduced pressure, and the mixed liquor extraction point liquid of dichloro Yue alkane and water is added into residue, simultaneously solvent is evaporated off in organic phase anhydrous sodium sulfate drying, crude product is obtained, through column chromatography for separation (silicagel column, petroleum ether:Ethyl acetate=30:1 (volume ratio）), obtain 1- (hexichol Yue yls) -3- methylpyrrolidin- 3- alcohol（1 g), the % of yield 52.0.
(5) (4S) -3- [l- hexichol Yue base -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2, the preparation of 6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester
To（R) -5- Yue oxygen carbonyls -2,6- dimethyl -4- (3- nitrobenzophenones) -1, Slow under 1 mL DMF, ice bath, which is added, in the dichloro Yue alkane solution of 4- dihydropyridine -3- carboxylic acids (3.58 g, 10.8 mmol) instills oxalyl chloride (2.74g slowly, 21.6 mmol), in 25 °C of reactions, until reaction is complete, oxalyl chloride is removed under reduced pressure, respectively by 1- (3,3- diphenyl propyl) -3- Yue base pyrrolidines -3- alcohol under ice bath cooling（1 g, 3.7 mmol) and DIPEA (1.4 g, 10.8 mmol) successively Slow be added dropwise to slowly in reaction bulb, in 25 °C of reactions, HPLC monitorings are complete until reaction, reaction solution is washed with water three times, filtrate is evaporated by organic phase through anhydrous sodium sulfate drying, suction filtration, through column chromatography for separation (silicagel column, petroleum ether：Ethyl acetate=15:1 (volume ratio））Obtain (4S) -3- [l- hexichol Yue base -3- Yue bases pyrrolidin-3-yl] 5- Yue base 2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acids esters (1.2 g), the % of yield 56.
Molecular formula： C34H35N306Molecular weight： 581.2
^-NMRCDMSO, 400 MHz) δ:9.19-9.13 (1 H, m), 8.01-7.89 (2 Η, m), 7.73-7.68 (4 Η, m), 7.58-7.53 (2 Η, m), 7.41-7.34 (6 Η, m), 4.93-4.89 (1 Η, s), 3.77-3.69 (2 Η, m), 3.62-3.42 (3 Η, m), 3.37-3.22 (3 Η, m), 2.49-2.48 (1 H, s), 2.28-1.99 (6 H, d), 1.50-1.35 (3 H, dd).Embodiment 24:(4S) -3- " l- (3,3- bis-（4- fluorophenyls）Propyl group) -3- methylpyrrolidin- 3- bases 1 5- methyl 2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters（Compound 27) preparation
Experimental procedure be the same as Example 15, but step（4) reactant 3 in, the small ethyl propionate of 3- diphenyl is replaced with the small ethyl propionate of 3,3- bis- (4- fluorine) phenyl, obtains compound 27. Mass spectrum (M+H)：646.3 ο refer to above-mentioned preparation method, can also prepare following compound:
..S000/ZT0ZN3/X3d ■909 Z OAV
..S000/ZT0ZN3/X3d ■909 Z OAV
II. the pharmacological activity test of the compounds of this invention
The beneficial effect of the compounds of this invention is expanded on further below by way of pharmacological experimental example, but this should not be interpreted as to the compounds of this invention only has following beneficial effect.Test example 1:The compounds of this invention is determined to L-type and T- type calcium channels blocking activity
1. test sample:The hydrochloride of compound 1, the hydrochloride of compound 2, compound 14, compound
15th, compound 16, compound 17, compound 19 and compound 20, self-control, its chemical name and structural formula are as mentioned before；
Positive control drug：Lercanidipine, Barnidipine, Amlodipine and Azelnidipine, it is purchased in market.
2. L is detected with T-shaped calcium channel inhibitor This experiment commission HD (HD:Brightness source biotechnology（Shanghai）Co., Ltd, HD Biosciences corporation) company completed by electrophysiological method, as a result see the table below 1 and 2.
Real long-mouth dog method：
With reference to Jung-Ha Lee, et. al, " Identification of T-Type alH Ca2+ Channels (Cav3.2) in Major Pelvic Ganglion Neurons". J Neurophysiol 87:2844-2850,2002 literature method.
Accurately weigh test sample, by 3 times step by step dilution relation make respectively it is final concentration of：
10 μΜ、 3 μΜ、 1 μΜ、 0.3 μΜ、 0.1 μΜ、 0.03 μΜ。
Τ-type detection：Neurons of Cerebral Cortex is separated from suckling mouse, culture is used to test after 7 days.Whole-cell patch-clamp recording technique record cell plasma electric current is applied at room temperature.Clamp current is 10s between -90 mV, arteries and veins, and the inward electric current activated since -20 mV is T-shaped calcium current
(ICa, T).
L-type is detected：From cavy separate left compartment muscle cell, cell in 8 hours be used for test.Whole-cell patch-clamp recording technique record cell plasma electric current is applied at room temperature.Clamp current is 10s between -80 mV, arteries and veins, and the inward electric current activated since 0 mV is L-type calcium current
(ω。
Liquid (mM) in electrode: CsCl 120, TEA-C1 20, CaCl21, EGTA-CsOH 11, Hepes 10, Mg-ATP 5, pH7.3;
TEA-C1:165.70 mg, cesium chloride：1010.16 mg, calcium chloride：7.35 mg, adenosine triphosphate magnesium： 126.80 mg, HEPES: 119.15 mg, EGTA: 209.22 mg, ddH20: 35 mL。
Mentioned component is completely dissolved in deionized water, adjusted pH value to 7.25 with 1 M cesium hydroxides, appropriate amount of deionized water is added and adjusts final volume to 50 mL;Regulation infiltration is depressed into 280 mOsm, and after 0.20 μ π ι filter filtering, packing is placed in -20 to I mL EP pipes.Saved backup in C.
The outer liquid (mM) of electrode:NaCl 135, CsC1 5.4, CaCl2 1.8 , MgCl21, Hepes 5, glucose 10, pH7.4. Sodium chloride:7890.00 mg, cesium chloride：909.14 mg, calcium chloride：264.64 mg, magnesium chloride： 203.30 mg, HEPES:1191.50 mg, glucose： 1981.70 mg, dd¾0: 980 mL。
Above-mentioned part is weighed up, 850 mL dd H are mixed in20, it is sufficiently dissolved using magnetic stirring apparatus.PH value is adjusted to 7.40 with 1 M sodium hydroxides, and adjusts final volume to 1000 mL.Osmotic pressure is adjusted to 290 mOsm (milli infiltrations mole）Afterwards, it is placed in the bottle of cleaning, is stored in standby in 4 °C of water tanks.
The T- types detection commission Chan Test Corporation of compound 19 and compound 20 are carried out as follows by FLIPR experimental methods.
Experimental method：
With reference to the literature methods of the Al of WO 2009/056934 p.48.
Accurately weigh test sample, by 3 times step by step dilution relation make respectively it is final concentration of：100 μ Μ, 30 μ Μ, 10 μ Μ, 3 μ Μ, 1 μ Μ, 03 μ Μ, Ο Ι μ Μ, 0.03 μ Μ, Ο Ο Ι μ Μ, 0003 μ Μ.
Τ-type detection：Clone people Cav3.2 in stable Η Ε Κ -293 cells, then carried out using the No- Wash kit of FLIPR Calcium 4 operation, cell culture medium is removed, in the HEPES solution of not calcium ions, the dyestuff for adding 20 is dyed, time 30min, 37 °C of temperature, the Slow fliud flushings of this not calcium ions include NaCl, 137mM; KC1, 0.5 mM; MgCl2mM, 1 mM; HEPES, 10 mM;Glucose, 10 mM, are adjusted pH to 7.4 with NaOH.After 30min, 30min is placed in room temperature, 5 μ compounds to be detected, solvent, or blank control is added.Compound is prepared with the Slow fliud flushings containing calcium ion, and Slow fliud flushings include KC1,135 mM; CaCl2, 10.8 mM; MgCl2, 1 mM; HEPES, 10 mM; glucose, 10 mM.The fluorescent value being collected into is analyzed, inhibiting rate is calculated, as a result see the table below 3.
3. experimental result and conclusion：
Inhibitory activity (electrophysiological method of the compounds of this invention of table 1 to L-type calcium channel）Test sample Ι 05ο(μΜ) ~
Lercanidipine-Barnidipine 0.58 The Azelnidipine 1.39 of Amlodipine 1.11
Nifedipine 0.3
Compound 14 0.59
Compound 15 1.28
Compound 16 0.59
Compound 17 0.93
From table 1, the compounds of this invention has the inhibition of stronger suppression comparison medicine living suitable to L-type calcium channel.Inhibitory activity of the compounds of this invention of table 2 to T- type calcium channels
Test sample Ι.50(μΜ)
Lercanidipine is more than 10
Barnidipine 8.15
Amlodipine 15.63
Azelnidipine 378.3
Nifedipine 1140
The hydrochloride 4.47 of compound 1
The hydrochloride 3.20 of compound 2
Compound 16 2.28
Inhibitory activity (FLIPR method) of the compounds of this invention of table 3 to Τ-type calcium channel
Barnidipine 30.80
Amlodipine>100
Compound 16 1.95 Compound 17 9.41
Compound 19 75.44
Compound 20 66.86
From table 2 and table 3, the compounds of this invention is significantly better than inhibitory activity of the positive control drug to T- type calcium channels to the inhibitory activity of T- type calcium channels, thus with preferable blood pressure lowering effect, and have1Dirty, cardioprotection, and Small side effects.
Test example 2:The internal antihypertensive activity experiment of the compounds of this invention
1. test sample:Compound 18, compound 21, compound 22, compound 23, compound 26, compound 19 and compound 20, self-control, its chemical name and structural formula are as mentioned before；
Positive control drug：Lercanidipine, Barnidipine, Amlodipine, Azelnidipine, Efonidipine and Manidipine, it is purchased in market.
2. experimental method：
The method experiment of folder tail is taken in internal antihypertensive activity experiment, and experimental method refers to day Yao Li Chi (F tia ph rm＆cot, japm) 97,115-126 (1991).
Medicine Lercanidipine to be measured, Barnidipine, Amlodipine, Azelnidipine, Efonidipine and Manidipine are accurately weighed respectively, after being dissolved with DMSO, the PEG400 of respective volume 50% is added, makes each medicine final concentration of lmg/ml, DMSO final concentration of 3%.
Testing compound 18 is accurately weighed respectively, and compound 21, compound 22, compound 23, compound 26 after being dissolved with DMSO, adds the PEG400 of respective volume 50%, and it is lmg/ml, DMSO final concentration of 3% to make each final compound concentration.
Test compounds compounds 19 and compound 20 are accurately weighed respectively, are suspended with 0.5% MC, and it is lmg/ml to make each final compound concentration.
Antihypertensive effect is detected：Male SHR (spontaneous hypertensive rats）, it is randomly divided into control group, administration group.Administration is filled, preceding 1 hour institute's measuring blood pressure is administered as basic blood pressure value before medicine. After administration, with soft grand BP-98A non-invasive blood pressure instruments measure respectively SHR upon administration 1,2,4,6,8 and 24 hours systolic pressure at totally 6 time points, heart rate and mean arterial pressures, testing result is shown in Table 4.
3. bright and conclusion is tied in experiment：
Antihypertensive activity of the compounds of this invention of table 4 to SHR
~ 7 ~ dosage size of animal Max Δ Μ Α Ρ ~ AMAP>20(mmHg)
(mg/kg, po) (）（MmHg scholar SEM) acting duration（h)
Note：Δ Μ Α Ρ are mean arterial pressure value after administration and the difference that preceding mean arterial pressure value is administered.From table 4, the compounds of this invention has good antihypertensive effect in SHR, maintains duration of the antihypertensive effect more than 20mmHg long compared with comparison medicine.
Test example 3:The internal antihypertensive activity experiment of the compounds of this invention
1. test sample:Compound 1, compound 2, compound 15, compound 16 and compound 17, self-control, its chemical name and structural formula are as mentioned before；
Positive control drug：Lercanidipine, Barnidipine, Amlodipine and Azelnidipine, It is purchased in market.
2. experimental method:
Internal antihypertensive activity experiment uses DSI experimental methods, with reference to the Al p. of WO 2009/056934
56。
Accurately weigh medicine Lercanidipine to be measured, Barnidipine, Amlodipine, Azelnidipine, Efonidipine and Manidipine, after being dissolved with DMSO, the PEG400 of respective volume 50% is added, makes each medicine final concentration of lmg/ml, DMSO final concentration of 3%.
Test compounds compounds 1 and compound 2 accurately are weighed, after being dissolved with DMSO, the PEG400 of respective volume 50% are added, it is lmg/ml, DMSO final concentration of 2% to make each final compound concentration.
Testing compound 15 accurately is weighed, after being dissolved with DMSO, the PEG400 of respective volume 50% is added, it is lmg/ml, DMSO final concentration of 3% to make each final compound concentration.
Testing compound 16 (+108.34 ° of optical activity) and compound 17 (+36.4 ° of optical activity optical activity) accurately are weighed, is suspended with 0.5% MC, it is lmg/ml to make each final compound concentration.
Antihypertensive effect is detected：Male SHR, row implanted device abdominal aorta implantation is recovered to be used to test after 7-10 d.Gastric infusion, is administered preceding 1 hour institute's measuring blood pressure as basic blood pressure value before medicine.After administration, with DSI implanted blood pressure telemetry system continuous monitoring 24h, free diet.Testing result is shown in Table 5.
3. experimental result and conclusion：
Antihypertensive activity of the compounds of this invention of table 5 to SHR
Dosage size of animal Max Δ Μ Α Ρ AMAP>20 (mmHg) make (mg/kg, po) (only）（MmHg scholar SEM) use the scholar 7 14 of duration (h) Lercanidipine 10 4 54
Barnidipine 10 4 60 ± 69
Amlodipine 10 4 48 ± 13 16
Azelnidipine 10 4 40 ± 5 11
The scholar 76 of compound 1 10 3 47
Compound 2 10 3 53 ± 7 16
Compound 15 10 3 56 ± 1 14 The compound 17 10 4 57 ± 5 16 of compound 16 10 4 57 ± 5 11
Note：Δ Μ Α Ρ for mean arterial pressure value after administration and mean arterial pressure value before administration difference from table 5, the compounds of this invention has good antihypertensive effect in SHR, maintains duration of the antihypertensive effect more than 20mmHg long compared with comparison medicine.

Claims (14)

  1. Acceptable salt or its stereoisomer in claim:
    R1And R4It is each independently selected from following one group of group：Amino, cyano group, and it is unsubstituted or by 1 to 3 substituent Q1The d_ replaced6Alkyl, d_4Alkoxy d.3Alkyl, C2_6Alkenyl or C2.6Alkynyl, and carbon atom therein can be optionally by 1 ~ 30, S (0)x、 N(H)X、 NCH3Or C (O) is replaced, wherein x is selected from 0,1 or 2; Q1Selected from following one group of group：Halogen, hydroxyl, amino, cyano group, carboxyl and alkoxy；
    R2Selected from unsubstituted or by 1 to 3 substituent Q2Substituted C1-6Alkyl, C3_8Cycloalkyl-alkyl or 3-8 circle heterocycles bases Co-6Alkyl, Q2Selected from following one group of group：Halogen, hydroxyl, amino,（^_6Alkoxy, and the C replaced by 1 to 3 halogen1-6Alkyl and d_6Alkoxy；
    R3Selected from following one group of group：Hydrogen, halogen, hydroxyl, cyano group, nitro and ^_6Alkylamidoalkyl；
    R5And R6It is each independently selected from unsubstituted or by 1 to 3 substituent Q3Substituted alkyl or C3_8Cycloalkyl C0_6Alkyl, Q3Selected from following one group of group：Halogen, hydroxyl, amino and C6Alkoxy；
    R7And R8It is each independently selected from following one group of group：Hydrogen, d_6Alkyl, it is unsubstituted or by 1 to 3 substituent Q4Substituted aryl Q) _6Alkyl, and it is unsubstituted or by 1 to 3 substituent Q4Substituted 3-8 circle heterocycles bases Co_6Alkyl, and R7And R8It is asynchronously hydrogen, Q4Selected from following one group of group：Halogen, hydroxyl, cyano group, nitro, amino, d_6Alkyl, 1 to 3！The alkyl of element substitution, C^6Alkoxy and d_6Alkylamidoalkyl；
    M is selected from 1,2 or 3, when m is 2 or 3, R3Can be with identical or different； n1And n2It is each independently selected from 1 to 5 integer, and n1And n2Can not be 2,4 or 5 simultaneously;And
    P and q are each independently selected from 0,1,2 or 3, but when q is 0, R7And R8Can not be phenyl simultaneously.
    2nd, compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein：
    R1And R4It is each independently selected from following one group of group：Amino, cyano group is unsubstituted or by 1 to 3 substituent Q1Substituted CMAlkyl, alkoxy d_2Alkyl, C2_4Alkenyl or C2_4Alkynyl, and carbon atom therein can be optionally by 1 ~ 30, S (0)x、N(H)x、NCH3Or C (O) is replaced, wherein X is selected from 0,1 or 2; Q1Selected from following one group of group：Halogen, hydroxyl, amino, carboxyl and CM alkoxies；And/or
    R2Selected from unsubstituted or by 1 to 3 substituent Q2Substituted d.4Alkyl, C3_6Cycloalkyl 0) _4The heterocyclic radical QM alkyl of alkyl or 3-6 member saturations, Q2Selected from following one group of group：Halogen, hydroxyl, amino,（Alkoxy, and replaced by 1 to 3 ι element（^_4Alkyl and CMAlkoxy；And/or
    R3Selected from following one group of group：Hydrogen, element, hydroxyl, cyano group, nitro and C^4Alkylamidoalkyl；And/or
    R5And R6It is each independently selected from unsubstituted or by 1 to 3 substituent Q3Substituted CMAlkyl or C3.6Cycloalkyl .4 alkyl, Q3Selected from following one group of group：Element, hydroxyl, amino and CM alkoxies；And/or
    R7And R8It is each independently selected from following one group of group：Hydrogen, CMAlkyl, it is unsubstituted or by 1 to 3 substituent Q4Substituted aryl C (M alkyl, and it is unsubstituted or by 1 to 3 substituent Q4Substituted 3-8 circle heterocycles base Q alkyl, and R7And R8It is asynchronously hydrogen, Q4Selected from following one group of group：Halogen, hydroxyl, amino, d.4Alkyl, the C of 1 to 3 halogen substitutionMAlkyl and d_4Alkoxy.
    3rd, compound as claimed in claim 2, its pharmaceutically acceptable salt or its stereoisomer, wherein：
    R1And R4It is each independently selected from following one group of group：Amino, cyano group, and do not taken Generation or by 1 to 3 substituent Q1Substituted CMAlkyl and (：Alkoxy, and carbon atom therein can optionally by 1 ~ 30,：^ (11 or（(0) replace, wherein X be selected from 0,1 or2； Q1Selected from following one group of group：Element, hydroxyl, amino and (^_4Alkoxy；
    R2Selected from following one group of group：It is unsubstituted or by 1 to 3 substituent Q2Substituted d_4Alkyl, cyclopropyl, cyclopropyl Yue bases, cyclopropylethyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, pyrrolidinyl Yue bases and morpholinyl methyl, Q2Selected from following one group of group：Fluorine, chlorine, hydroxyl, amino, CMAlkoxy, and the C replaced by 1 to 3 fluorine and/or chlorineMAlkyl and（1-4Alkoxy；
    R3Selected from following one group of group：Hydrogen, element and nitro；
    R5And R6It is each independently selected from unsubstituted or by 1 to 3 substituent Q3Substitution
    CM alkyl or C3.6Cycloalkyl C0_2Alkyl, Q3Selected from following one group of group：Halogen, hydroxyl, amino and C alkoxies；
    R7And R8It is each independently selected from hydrogen, Yue bases, ethyl is unsubstituted or by 1 to 3 substituent Q4Substituted aryl 0) _2Alkyl, and it is unsubstituted or by 1 to 3 substituent Q4Substituted 3-6 circle heterocycles bases Co_2Alkyl, and R7And R8It is asynchronously hydrogen, Q4Selected from following one group of group：The C of halogen, hydroxyl, amino, alkyl, and 1 to 3 halogen substitution1-3Alkyl and alkoxy；
    M is each independently selected from 1,2 or 3, when m is 2 or 3, R3Can be with identical or different；
    η1And n2It is each independently selected from 1,2 or 3, and n1And n2Can not be 2 simultaneously;And
    P and q are each independently selected from 0,1,2 or 3, but when q is 0, R7And R8Can not be phenyl simultaneously.
    4th, compound as claimed in claim 3, its pharmaceutically acceptable salt or its stereoisomer, wherein：
    R1And R4It is each independently selected from following one group of group：It is unsubstituted or by 1 to 3 substituent Q1Substituted Yue bases, ethyl and ethyoxyl Yue bases, and carbon atom therein can be optionally by 130, N (H)XOr C (O) is replaced, wherein X is selected from 1 or 2; Q1Selected from following one group of base Group：Halogen, hydroxyl, amino, methoxyl group and ethyoxyl；
    R2Selected from following one group of group：It is unsubstituted or by 1 to 3 substituent Q2Substituted methyl, ethyl, isopropyl, cyclopropyl, cyclopropyl Yue bases, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, pyrrolidinyl Yue bases and morpholinyl Yue bases, Q2Selected from following one group of group：Fluorine, chlorine, hydroxyl, amino,（Alkoxy, and the C replaced by 1 to 3 fluorine and/or chlorine1-4Alkyl and C1-4Alkoxy；
    R3Selected from following one group of group：Hydrogen, fluorine, chlorine and nitro；
    R5And R6It is each independently selected from unsubstituted or by 1 to 3 substituent Q3Substituted Yue bases or ethyl, Q3Selected from following one group of group：Fluorine, chlorine, hydroxyl, amino, Yue epoxides and ethyoxyl；
    R7And R8It is each independently selected from following one group of group：Hydrogen, Yue bases, ethyl, and it is unsubstituted or by 1 to 3 substituent Q4Substituted phenyl CQ_2Alkyl, pyridine radicals CQ.2Alkyl, furyl C._2Alkyl, thienyl .2 alkyl, pyrrole radicals C..2Alkyl, thiazolyl C..2Alkyl and thiadiazolyl group Co.2Alkyl, and R7And R8It is asynchronously hydrogen, Q4Selected from following one group of group：Fluorine, chlorine, hydroxyl, amino, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, Yue epoxides and ethyoxyl；
    M is selected from 1,2 or 3, when m is 2 or 3, R3Can be with identical or different； n1For 1,2 or 3, n2For 1;
    P and q are each independently selected from 0,1,2 or 3, when q is 0, R7And R8Can not be phenyl simultaneously.
    5th, compound as claimed in claim 4, its pharmaceutically acceptable salt or its stereoisomer：
    Wherein, R1And R4It is each independently selected from unsubstituted or by 1 to 3 substituent Q1Substituted Yue bases, ethyl or ethoxyl methyl, Q1Selected from fluorine, chlorine, amino, Yue epoxides or ethyoxyl；
    R2Selected from unsubstituted or by 1 to 3 substituent Q2Substituted methyl or ethyl, Q2Selected from fluorine, chlorine, methyl, methoxyl group, or replaced by 1 to 3 fluorine, chlorine Yue epoxides, ethyoxyl； R3Selected from hydrogen, chlorine or nitro；
    R5Selected from unsubstituted or by 1 to 3 substituent Q3Substituted methyl or ethyl, Q3Selected from fluorine, chlorine, hydroxyl or amino；
    R6Selected from unsubstituted or by 1 to 3 substituent Q3Substituted methyl, Q3Selected from fluorine, chlorine, hydroxyl or amino；
    R7And R8It is each independently selected from hydrogen, it is unsubstituted or by 1 to 3 substituent Q4Substituted phenyl, benzyl, pyridine radicals, furyl, thienyl, thiazolyl or pyrrole radicals, and R7And R8It is asynchronously hydrogen,
    Q4Selected from fluorine, chlorine, hydroxyl, amino, Yue bases, trifluoro Yue bases or Yue epoxides；M is 1;
    n1For 1 or 2, n2For 1;
    P is and q is each independently selected from 0,1 or 2, when q is 0, R7And R8Can not be phenyl simultaneously.
    6th, compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein compound are selected from：
    Structural formula of compound chemical name
    (5) -3- [CS)-l- (2,2- diphenyl-ethyls）- 3- methylpyrrolidin- 3- yls] 5- methyl 2,6- bis-
    20
    Yue bases .4- (3-nitrobenzophenone)-Isosorbide-5-Nitrae-dihydro pyrrole Pyridine -3,5- dicarboxylic esters
    (4S)-3- [3- Yue bases-1-(3- phenylpropyls) pyrrolidines
    。
    21 adopted 0 Yi Yi -3- bases] 5- methyl 2, Yue bases -4- (the 3- nitro people H people of 6- bis-c¾Phenyl) -1,4- dichloropyridine-3,5-carboxylic-acid esters
    (45) -3- (3- Yue base -1- phenethyl pyrrolidines -3-
    22 bases）5- methyl 2, Yue bases -4- (the 3- nitros of 6- bis-
    H phenyl) -1,4- dichloropyridine-3,5-carboxylic-acid esters
    (4 3- [1- (3,5- difluorobenzyls) -3- methyl p ratios cough up alkane -3- bases] 5- Yue base 2,6- dimethyl
    23
    People A CH, -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- H dicarboxylic esters
    CS 3- [() small (3,5- difluorobenzyl) -3- Yue bases pyrrolidin-3-yl] 5- methyl 2,6- diformazans
    24
    Base -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine
    H -3,5- dicarboxylic esters
    (5) -3 1- (3,5- difluorobenzyls) -3- methyl
    。
    25 t, pyrrolidin-3-yl] 5- methyl 2, the Yue bases of 6- bis-
    - 4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5-
    H dicarboxylic esters
    (4S)-3-[l
    26-hexichol Yue base-3- Yue base pyrrolidines
    - 3- bases] 5- methyl 2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester
    Structural formula of compound chemical name
    (5) -3- [(small (pyridin-3-yl methyl) pyrrolidin-3-yl of 5 3- ethyls] 5- Yue bases 2- (2- amino
    77
    Ethyoxyl）Methyl -4- (2- chlorphenyls) -6- Yue base -1,4- dichloropyridine-3,5-carboxylic-acid esters
    7th, compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein compound are selected from：
    3- (1- benzyl -3- Yue bases pyrrolidin-3-yl) 5- methyl 2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    3- [1- (3,3- diphenylpropyl) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    3- (1- benzyl -3- Yue bases pyrrolidin-3-yl) 5- ethyls 2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    3- [1- (3,3- diphenylpropyl) -3- Yue bases pyrrolidin-3-yl] 5- ethyls 2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    3- (1- phenethyl -3- Yue base pyrrolidin-3-yls）5- methyl 2,6- bis- Yue bases -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters；
    3- [1- (2,2- Diphenethyl) -3- Yue bases pyrrolidin-3-yl] 5- methyl 2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    3- (1- benzyl -3- methylpyrrolidin- 3- yls) 5- Yue bases 2- [(2- amino ethoxies）Yue yls] -4- (2- chlorophenyls) -6- methyl -1,4- dichloropyridine-3,5-carboxylic-acid esters；
    3- [1- (3,3- diphenylpropyl) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2- [(2- amino ethoxies) Yue yls] _ 4- (2- chlorophenyls) -6- Yue base-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic esters；
    3- [1- (4- Fluoro-benz rLls) -3- Yue bases pyrrolidin-3-yl] 5- methyl 2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    3- [1- (4- Yue oxy-benzyls)-3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2,6- dimethyl-4- (3- nitrobenzophenones)-1,4- dihydropyridines-3,5-dicarboxylic ester； 3- [l- (3,3- bis- (4- difluorophenyls) propyl group) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2, the Yue bases of 6- bis- _ 4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    (4i) -3- (l- benzyl -3- Yue base pyrrolidin-3-yls）5- Yue bases 2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    (4<S) -3- (l- benzyl -3- Yue base pyrrolidin-3-yls）5- Yue bases 2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    (4 ) -3- [l- (3,3- diphenyl propyl) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2, the Yue bases of 6- bis- _ 4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    (S 3- [l- (3,3- diphenyl propyl) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    (5) -3- [(5) small (3,3- diphenyl propyl) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2, the Yue bases of 6- bis- _ 4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    0S) -3- [CR)-l- (3,3- diphenyl propyl) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2,6- dimethyl _ 4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    (45 3- [1- (2,2- diphenyl-ethyl) -3- methylpyrrolidin- 3- yls] 5- Yue bases 2, the Yue bases of 6- bis-
    - 4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters；
    (S) the Yue bases of -3- [(R)-l- (2,2- diphenyl-ethyls) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2,6- bis- _ 4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters；
    (5) -3- [(5) -1- (2,2- diphenyl-ethyl) -3- Yue bases pyrrolidin-3-yl] 5- methyl 2,6- bis- Yue bases -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    (4S) -3- [3- Yue bases -1- (3- phenylpropyls) pyrrolidin-3-yl] 5- Yue bases 2,6- bis- Yue bases -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters；
    (45) -3- (3- methyl isophthalic acids-phenethyl pyrrolidin-3-yl）5- Yue bases 2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；
    (45) the Yue bases of -3- [1- (3,5- difluorobenzyls) -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2,6- bis-
    - 4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters；
    (4S) -3- [l- hexichol Yue base -3- Yue bases pyrrolidin-3-yl] 5- Yue bases 2,6- dimethyl -4- (3- nitrobenzophenones)-Isosorbide-5-Nitrae-dihydropyridine -3,5- dicarboxylic ester；And (45 3- [1- ((the 4- difluorophenyls of 3,3- bis-）Propyl group) -3- Yue bases pyrrolidin-3-yl] 5- Yue base 2,6- dimethyl -4- (3- nitrobenzophenones) -1,4- dichloropyridine-3,5-carboxylic-acid esters.
    8th, the preparation method of the logical formula (I) compound of claim 1, comprises the following steps：Reaction process：
    Or
    Intermediate 1-1 intermediates 1-2
    ( I )
    R in reaction process1 R2、 R3、 R4、 R5、 R6、 R7、 R8、 m、 n1 , n2, p and q it is identical with the definition in claim 1；2=R of raw material5MgX, wherein X are Br or I；Raw material 2'=R5MgI, raw material 3=HCkff¾ R；
    0 R8Step 1：
    Raw material 1 is occurred nucleophilic substitution in low temperature with raw material 2 and obtain intermediate 1;Or make raw material Γ and raw material 2, generation nucleophilic substitution obtains intermediate 1-1, it is set to carry out salt-forming reaction with sour HA, obtain intermediate 1-2, coupling reaction is occurred into for obtained intermediate 1-2 and raw material 3, intermediate 1-3 is obtained, then intermediate 1-3 is reduced with reducing agent, intermediate 1 is obtained;Step 2:
    Raw material 4, raw material 5 and raw material 6 is flowed back in organic solvent and carry out condensation reaction, obtain intermediate 2-1, it is hydrolyzed in the presence of a base, obtain intermediate 2;And
    Step 3:
    Intermediate 2 is reacted in low temperature and acid halide reagents, reaction then is hydrolyzed in low temperature in the basic conditions with intermediate 1, formula is obtained（I) compound.
    9th, pharmaceutical composition, contains the compound described in any one of claim 1 ~ 7, its pharmaceutically acceptable salt or its stereoisomer.
    10th, pharmaceutical composition as claimed in claim 9, also comprising selected from following therapeutic agent：Angiotensin-ii antagonist or its pharmaceutically acceptable salt, including Losartan, Valsartan, Irbesartan, Olmesartan, Candesartan；HMG-Co-A reductase inhibitors or its pharmaceutically acceptable salt, including Lovastatin, Simvastatin, Pravastatin, mevastatin, Fluvastatin, Atorvastatin, cerivastatin, rosuvastatin；Aldosterone receptor antagonist（) or its pharmaceutically acceptable salt, including spirolactone, eplerenone MRA；Angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) double inhibitor or its pharmaceutically acceptable salt, including captopril, alacepril, enalapril, lisinopril, training stamp Puli, Ramipril, quinapril, Delapril, Cilazapril, benazepil, Spirapril, Trandolapril, Moexipril, Imidapril, fosinopril；Antidiabetic, including the sour Egelieting of diformazan Chinese guanidine, glibenclamide, Glipizide, Glibornuride, gliclazide, gliquidone, Xi Gelieting, vildagliptin, BMS-477118, benzene Yue, Li Nalieting；Slimming drugs；Endothelin receptor antagonists, including Bosentan；CETP inhibitor；Na-K-ATP enzyme membrane pump inhibitors；β-tight upper parathyrine energy acceptor inhibitor, including Betaloc, Carvedilol； α- Adrenergic receptor blocking agent, including prazosin, Terazosin, Doxazosin；Neutral endopeptidase
    (NEP) inhibitor and inotropic agent.
    11. pharmaceutical preparation, is pharmaceutically acceptable any formulation containing the compound described in any one of claim 1 ~ 7, its pharmaceutically acceptable salt or its stereoisomer and one or more pharmaceutical carriers.
    12. compound, its pharmaceutically acceptable salt or its stereoisomer as described in any one of claim 1 ~ 7 prepare be used to treating/or prevention injury of kidney, the medicine of cardiovascular and/or endocrine system disease in application.
    13. application as claimed in claim 12, wherein the disease is selected from hypertension, heart failure, miocardial infarction, angina pectoris, cardiomegaly, myocarditis, cardiovascular fibrosis, pressoreceptor dysfunction, excessive body fluid and cardiac arrhythmia, primary/Secondary cases aldehyde ketone increase disease, Addison's disease, the emerging syndrome in storehouse and Bart's formula syndrome.
    14. treatment/or prevention injury of kidney, the method for cardiovascular and/or endocrine system disease, including the step of give the mammal for needing this treatment by the compound described in any one of claim 1 ~ 7, its pharmaceutically acceptable salt or its stereoisomer；The disease is selected from following one group：Hypertension, heart failure, miocardial infarction, angina pectoris, cardiomegaly, myocarditis, cardiovascular fibrosis, pressoreceptor dysfunction, excessive body fluid and cardiac arrhythmia, primary/secondary aldosteronism, Addison's disease, the emerging syndrome in storehouse and Bart's formula syndrome.
    International application No.
    INTERNATIONAL SEARCH REPORT
    PCT/CN2012/000577
    A. CLASSIFICATION OF SUBJECT MATTER
    See the extra sheet
    According to International Patent Classification (PC) or to both national classification and IPC
    B . FIELDS SEARCHED
    Minimum documentation searched (classification system followed by classification symbols)
    IPC: C07D 401/-； A61 K 31 /-
    Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
    Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
    CNPAT, CNKI, WPI, EPODOC, CA: dihydropyridine, alkoxycarbonyl, hypertension, calcium, Ca
    C. DOCUMENTS CONSIDERED TO BE RELEVANT
    Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
    X KOBAYASHI, Takashi et al. Novel 2-amino-l, 4-dihydropyridine calcium antagonists. Π 1-7,9-13
    Synthesis and antihypertensive effects of 2-amino-l, 4- dihydropyridine derivatives having
    Ν,Ν-dialkylaminoalkoxycarbonyl groups at 3- and/or 5-position. Chemical & Pharmaceutical
    Bulletin. 1995, vol. 43, no. 5, pages 797-817
    table 1, compound 1 , right column paragraph 2 in page 797, fig. 1
    Y
    13 Further documents are listed in the continuation of Box C. 13 See patent family annex.
    Special categories of cited documents: T" later document published after the international filing date or priority date and not in conflict with the application but
    "A" document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention
    " E, earlier application or patent but published on or after the " X " document of particular relevance; the claimed invention international filing date cannot be considered novel or cannot be considered to involve an inventive step when the document is taken alone
    " L, document which may throw doubts on priority claim (s) or
    "Y" document of particular relevance; the claimed invention which is cited to establish the publication date of another
    cannot be considered to involve an inventive step when the citation or other special reason (as specified) document is combined with one or more other such document referring to an oral disclosure, use, exhibition or documents, such combination being obvious to a person other means skilled in the art
    " p, document published prior to the international filing date " document member of the same patent family
    but later than the priority date claimed
    Form PCT ISA/210 (second sheet) (July 2009)
    Form PCT ISA/210 (continuation of second sheet ) (July 2009)
CN201280020936.XA 2011-04-29 2012-05-02 Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylate derivatives and preparation and application thereof Active CN103649075B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201280020936.XA CN103649075B (en) 2011-04-29 2012-05-02 Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylate derivatives and preparation and application thereof

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CN201110109496.2 2011-04-29
CN201110109496 2011-04-29
CN2011101094962 2011-04-29
CN201280020936.XA CN103649075B (en) 2011-04-29 2012-05-02 Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylate derivatives and preparation and application thereof
PCT/CN2012/000577 WO2012146067A1 (en) 2011-04-29 2012-05-02 1,4-dihydropyridine -3,5-dicarboxylate derivatives, preparation methods and uses thereof

Publications (2)

Publication Number Publication Date
CN103649075A true CN103649075A (en) 2014-03-19
CN103649075B CN103649075B (en) 2016-05-25

Family

ID=47071594

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201280020936.XA Active CN103649075B (en) 2011-04-29 2012-05-02 Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylate derivatives and preparation and application thereof

Country Status (5)

Country Link
US (1) US9198902B2 (en)
EP (1) EP2703398B1 (en)
JP (1) JP5859115B2 (en)
CN (1) CN103649075B (en)
WO (1) WO2012146067A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109721596A (en) * 2017-10-27 2019-05-07 广东东阳光药业有限公司 The dihydropyridine compounds and application thereof that phenyl replaces
CN117538462A (en) * 2024-01-10 2024-02-09 地奥集团成都药业股份有限公司 Method for detecting related substances of amlodipine benazepril capsules

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103588700B (en) * 2013-10-16 2015-04-29 齐鲁工业大学 Method for resolving barnidipine mother nucleus by using glucosamine as resolving agent
WO2017063307A1 (en) * 2015-10-13 2017-04-20 山东轩竹医药科技有限公司 Preparation method for 1,4-dihydropyridine-3,5-dicarboxylate derivative, and intermediate
CN108689904B (en) * 2017-04-12 2022-06-17 轩竹生物科技股份有限公司 Preparation method and application of chiral heterocyclic tertiary alcohol intermediate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4639522A (en) * 1982-10-15 1987-01-27 Kyowa Hakko Kogyo Co., Ltd. 1-benzyl-3,5-dimethyl-4-piperdyl ester of a Hantzsch dihydropyridine
CN87107150A (en) * 1986-10-09 1988-05-04 三共株式会社 Dihydrogen pyridine derivative and its production and use

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01139577A (en) * 1987-10-28 1989-06-01 Sankyo Co Ltd 1,4-dyhydropyridine derivative
WO2009056934A1 (en) 2007-10-31 2009-05-07 Pfizer Products Inc. 1,4-dihydronaphthyridine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4639522A (en) * 1982-10-15 1987-01-27 Kyowa Hakko Kogyo Co., Ltd. 1-benzyl-3,5-dimethyl-4-piperdyl ester of a Hantzsch dihydropyridine
CN87107150A (en) * 1986-10-09 1988-05-04 三共株式会社 Dihydrogen pyridine derivative and its production and use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TADAO SHIBANUMA ET AL.: "Synthesis of optically avtive 2-(N-benzyl-N-methylamino)ethyl methyl 2,6-dimethyl-4-（m-nitrophenyl）-1,4-dihydropyridine-3,5-dicarboxylate(Nicardipine)", 《CHEM. PHARM. BULL.》 *
TAKASHI KOBAYASHI ETAL.,: "Novel 2-amino-1,4-dihydropyridine calcium antagonists.Ⅱ.Synthesis anf antihypertensive effects of 2- amino-1,4-dihydropyridine derivatives Having N,N-dialkylaminoalkoxycarbonyl groups at 3-and/or 5-position", 《CHEM. PHARM. BULL.》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109721596A (en) * 2017-10-27 2019-05-07 广东东阳光药业有限公司 The dihydropyridine compounds and application thereof that phenyl replaces
CN109721596B (en) * 2017-10-27 2020-12-18 广东东阳光药业有限公司 Phenyl-substituted dihydropyridines and their use
CN117538462A (en) * 2024-01-10 2024-02-09 地奥集团成都药业股份有限公司 Method for detecting related substances of amlodipine benazepril capsules
CN117538462B (en) * 2024-01-10 2024-03-26 地奥集团成都药业股份有限公司 Method for detecting related substances of amlodipine benazepril capsules

Also Published As

Publication number Publication date
JP2014512398A (en) 2014-05-22
US9198902B2 (en) 2015-12-01
US20140045896A1 (en) 2014-02-13
CN103649075B (en) 2016-05-25
EP2703398A4 (en) 2014-10-01
WO2012146067A1 (en) 2012-11-01
JP5859115B2 (en) 2016-02-10
EP2703398B1 (en) 2017-12-13
EP2703398A1 (en) 2014-03-05

Similar Documents

Publication Publication Date Title
DK1757582T3 (en) Arylalkylamines AND MANUFACTURING METHOD THEREOF
CA2511970C (en) Urea derivatives useful in the treatment of heart failure
CA3079617A1 (en) Antagonists of the muscarinic acetylcholine receptor m4
EP2401265B1 (en) Derivatives of 1-pyri(mid)in-2-yl-pyrazole-4-carboxylic acid which are useful for therapy or prophylaxis of cardiovascular diseases
TWI357902B (en) Dipeptidyl peptidase-iv inhibiting compounds, meth
CN104718189A (en) Pyrrole sulfonamide derivative, preparation method for same, and medical application thereof
CN105237527B (en) Benzimidizole derivatives and preparation method thereof and medical usage
CA2867114C (en) Piperidine derivatives for gpr119 agonist
CN101090888A (en) 4-aminopiperidine derivatives
CN103649075A (en) 1,4-dihydropyridine-3,5-dicarboxylate derivatives, preparation methods and uses thereof
TWI295290B (en) Novel pyrrolidine-3,4-dicarboxamide derivatives
WO2020132016A1 (en) Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
CA3163933A1 (en) Antagonists of the muscarinic acetylcholine receptor m4
AU2018313802A1 (en) Antagonists of the muscarinic acetylcholine receptor M4
CA3106490A1 (en) [1,2,4]triazolo[1,5-a]pyridine compound as jak inhibitor and use thereof
JP2023535932A (en) tricyclic heterocycle
EP1557414B1 (en) Isoquinoline compounds and medicinal use thereof
CN103450163B (en) Indazole compounds, its preparation method and its medicinal usage
CA2930850C (en) Amide derivatives for gpr119 agonist
CN114206836A (en) Novel pyrrole compounds
CN101918398A (en) 4,4-disubstituted piperidines
CN102491929B (en) 1-hydroxy-2-ketopyrrolidine compound and preparation method and application thereof
CN106046101A (en) Glycogen phosphorylase inhibitor and preparation method and application thereof
RU2297411C2 (en) Isoquinoline compounds, intermediate compounds, methods for their preparing and using
AU2013275090B2 (en) Piperidine derivatives for GPR119 agonist

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20171227

Address after: Room 4905, exhibition square, 1 Hong Kong Bay Road, Wan Chai, Hongkong, China

Co-patentee after: Shandong Xuanzhu Medical Technology Co., Ltd.

Patentee after: Sihuan Pharmaceutical Holdings Group Ltd

Address before: Tianchen Avenue, Ji'nan hi tech Development Zone of Shandong Province, No. 2518 250101

Patentee before: Shandong Xuanzhu Medical Technology Co., Ltd.

TR01 Transfer of patent right
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20190214

Address after: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor

Patentee after: Hainan Xuanzhu Pharmaceutical Technology Co., Ltd.

Address before: Room 4905, Office Building, Exhibition Plaza, 1 Harbour Road, Wanchai, Hong Kong, China

Co-patentee before: Shandong Xuanzhu Medical Technology Co., Ltd.

Patentee before: Sihuan Pharmaceutical Holdings Group Ltd

CP03 Change of name, title or address
CP03 Change of name, title or address

Address after: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province 203c507

Patentee after: Xuanzhu Biotechnology Co., Ltd

Address before: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor

Patentee before: Hainan Xuanzhu Pharma Co.,Ltd.

CP01 Change in the name or title of a patent holder
CP01 Change in the name or title of a patent holder

Address after: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park 203c507, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province

Patentee after: Xuanzhu Biotechnology Co.,Ltd.

Address before: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park 203c507, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province

Patentee before: Xuanzhu Biotechnology Co.,Ltd.